HRP940769A2 - (s)(+)-2-ethoxy-4-(n-(1-(2-piperidinophenyl)-3-methyl-1-butyl)-aminocarbonylmethyl)benzoic acid, medicines containing them, that compound and processes for the preparation thereof - Google Patents
(s)(+)-2-ethoxy-4-(n-(1-(2-piperidinophenyl)-3-methyl-1-butyl)-aminocarbonylmethyl)benzoic acid, medicines containing them, that compound and processes for the preparation thereof Download PDFInfo
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- HRP940769A2 HRP940769A2 HRP-1136/91A HRP940769A HRP940769A2 HR P940769 A2 HRP940769 A2 HR P940769A2 HR P940769 A HRP940769 A HR P940769A HR P940769 A2 HRP940769 A2 HR P940769A2
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- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 title claims description 47
- 150000001875 compounds Chemical class 0.000 title claims description 38
- 238000000034 method Methods 0.000 title claims description 19
- 238000002360 preparation method Methods 0.000 title claims description 15
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- 239000003814 drug Substances 0.000 title claims description 4
- 230000008569 process Effects 0.000 title claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 88
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 75
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 62
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 33
- 238000002844 melting Methods 0.000 claims description 27
- 230000008018 melting Effects 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 25
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 14
- 230000007062 hydrolysis Effects 0.000 claims description 11
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- 230000001681 protective effect Effects 0.000 claims description 8
- CARYLRSDNWJCJV-HNNXBMFYSA-N (1s)-3-methyl-1-(2-piperidin-1-ylphenyl)butan-1-amine Chemical group CC(C)C[C@H](N)C1=CC=CC=C1N1CCCCC1 CARYLRSDNWJCJV-HNNXBMFYSA-N 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 150000007522 mineralic acids Chemical class 0.000 claims description 7
- 150000007524 organic acids Chemical class 0.000 claims description 7
- 235000005985 organic acids Nutrition 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
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- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
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- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 238000001149 thermolysis Methods 0.000 claims description 3
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 230000000269 nucleophilic effect Effects 0.000 claims description 2
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- 239000003826 tablet Substances 0.000 description 35
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
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- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 9
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
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- PMOWTIHVNWZYFI-WAYWQWQTSA-N cis-2-coumaric acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1O PMOWTIHVNWZYFI-WAYWQWQTSA-N 0.000 description 7
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- FTCMVLQJMIXDSI-VWLOTQADSA-N ethyl 2-ethoxy-4-[2-[[(1s)-3-methyl-1-(2-piperidin-1-ylphenyl)butyl]amino]-2-oxoethyl]benzoate Chemical compound C1=C(OCC)C(C(=O)OCC)=CC=C1CC(=O)N[C@@H](CC(C)C)C1=CC=CC=C1N1CCCCC1 FTCMVLQJMIXDSI-VWLOTQADSA-N 0.000 description 6
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
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- 229910052757 nitrogen Inorganic materials 0.000 description 5
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 5
- OTGSESBEJUHCES-UHFFFAOYSA-N 2-(3-ethoxy-4-ethoxycarbonylphenyl)acetic acid Chemical compound CCOC(=O)C1=CC=C(CC(O)=O)C=C1OCC OTGSESBEJUHCES-UHFFFAOYSA-N 0.000 description 4
- FAEKWTJYAYMJKF-HSZRJFAPSA-N 2-ethoxy-4-[2-[[(1r)-3-methyl-1-(2-piperidin-1-ylphenyl)butyl]amino]-2-oxoethyl]benzoic acid Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-HSZRJFAPSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
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- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
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- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
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- DIOBIOPCRMWGAT-NSHDSACASA-N (2s)-2-[(3,5-dinitrobenzoyl)amino]-4-methylpentanoic acid Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 DIOBIOPCRMWGAT-NSHDSACASA-N 0.000 description 1
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- FAEKWTJYAYMJKF-UHFFFAOYSA-N 2-ethoxy-4-[2-[[3-methyl-1-(2-piperidin-1-ylphenyl)butyl]amino]-2-oxoethyl]benzoic acid Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)NC(CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-UHFFFAOYSA-N 0.000 description 1
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- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
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- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
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- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
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- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
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- WPDGFKWDLXLZQM-UHFFFAOYSA-N chloroethane formic acid Chemical compound C(=O)O.C(C)Cl WPDGFKWDLXLZQM-UHFFFAOYSA-N 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
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- 238000010918 diastereoselective addition Methods 0.000 description 1
- 238000011917 diastereoselective reduction Methods 0.000 description 1
- WLXALCKAKGDNAT-UHFFFAOYSA-N diazoethane Chemical compound CC=[N+]=[N-] WLXALCKAKGDNAT-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
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- VRZVPALEJCLXPR-UHFFFAOYSA-N ethyl 4-methylbenzenesulfonate Chemical compound CCOS(=O)(=O)C1=CC=C(C)C=C1 VRZVPALEJCLXPR-UHFFFAOYSA-N 0.000 description 1
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- CGCRZBDCOLHGQV-LGMDPLHJSA-N n-[(z)-3-methyl-1-(2-piperidin-1-ylphenyl)but-1-enyl]acetamide Chemical compound CC(C)\C=C(/NC(C)=O)C1=CC=CC=C1N1CCCCC1 CGCRZBDCOLHGQV-LGMDPLHJSA-N 0.000 description 1
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- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
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- 239000011591 potassium Substances 0.000 description 1
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- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
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- 230000002459 sustained effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 238000004809 thin layer chromatography Methods 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
Landscapes
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
U EP-B-0,147,850 je među ostalima opisana i racemična 2-etoksi-4-[N-[1-(2-piperidino-fenil)-3-metil-1-butil] amino karbonilmetil]-benzojeva kiselina (kod br. : AG-EE 388 ZW) formule EP-B-0,147,850 describes, among others, racemic 2-ethoxy-4-[N-[1-(2-piperidino-phenyl)-3-methyl-1-butyl] aminocarbonylmethyl]-benzoic acid (code no. : AG-EE 388 ZW) formulas
[image] [image]
i u EP-B-0,207,331 dva daljnja polimorfna oblika ovog spoja. Ovaj spoj i njegove fiziološko prihvatljive soli imaju dragocjena farmakološka svojstva, naime učinak na međumetabolizam, posebno učinak sniženja krvnog tlaka. and in EP-B-0,207,331 two further polymorphic forms of this compound. This compound and its physiologically acceptable salts have valuable pharmacological properties, namely the effect on intermediate metabolism, especially the effect of lowering blood pressure.
Obadva enantiomera ovog spoja, naime (S)-(+)-2-etoksi-4-[N-[1-(2-piperidino-fenil)-3-metil-1-butil]amino karbonil metil]-benzojeva kiselina, (kod br. : AG-EE 623 ZW) i (R)-(-)-2-etoksi-4-[N-[1-(2-piperidino-fenil)-3-metil-1-butil] aminokarbonilmetil]-benzojeva kiselina (kod br. : AG-EE 624 ZW), istražili smo učinak na sniženje krvnog šećera na ženkama štakora. Both enantiomers of this compound, namely (S)-(+)-2-ethoxy-4-[N-[1-(2-piperidino-phenyl)-3-methyl-1-butyl]amino carbonyl methyl]-benzoic acid, (code no.: AG-EE 623 ZW) and (R)-(-)-2-ethoxy-4-[N-[1-(2-piperidino-phenyl)-3-methyl-1-butyl] aminocarbonylmethyl] -benzoic acid (code no.: AG-EE 624 ZW), we investigated the effect on lowering blood sugar in female rats.
Iznenađujuće smo ustanovili, da je (S)-enantiomer (AG-EE 623 ZW) učinkovit enantiomer i da njegov učinak pri štakoru traje više od 6 sati. Surprisingly, we found that the (S)-enantiomer (AG-EE 623 ZW) is an effective enantiomer and that its effect lasts more than 6 hours in rats.
Na osnovi ovih rezultata na štakoru za čovjeka se nudi isključiva uporaba AG-EE 623 ZW, čime možemo smanjiti dozu za 50 % u usporedbi s dozom AG-EE 388 ZW. Ovo, i relativno dugotrajno djelovanje, mogli smo potvrditi pri čovjeku. Pored toga smo kod humanih proučavanja ustanovili, da AG-EE 623 ZW ponovno ima iznenađujuća farmakokinetička svojstva koja se nisu mogla predvidjeti na osnovi podataka za AG-EE 388 ZW. AG-EE 623 ZW pokazuje dakle iznenađujuće terapeutske prednosti u usporedbi s racematom AG-EE 388 ZW. Based on these results in the rat, the exclusive use of AG-EE 623 ZW is proposed for humans, which allows us to reduce the dose by 50% compared to the dose of AG-EE 388 ZW. We were able to confirm this, and relatively long-term action, in humans. In addition, we found in human studies that AG-EE 623 ZW again has surprising pharmacokinetic properties that could not be predicted based on the data for AG-EE 388 ZW. AG-EE 623 ZW therefore shows surprising therapeutic advantages compared to racemate AG-EE 388 ZW.
Iznenađujući nalazi na čovjeku su: Surprising findings on humans are:
(a) Razine AG-EE 623 ZW padaju brže prema nuli nego razine AG-EE 388 ZW, čak pri jednakoj apsolutnoj dozi, što nije bilo očekivano na osnovi relativno dugotrajnog djelovanja. (a) AG-EE 623 ZW levels fall more rapidly towards zero than AG-EE 388 ZW levels, even at the same absolute dose, which was not expected based on the relatively long duration of action.
(b) Glede na postignuto sniženje krvnog šećera nastaju znatno niži nivoi plazme AG-EE 623 ZW nego što bi bilo za očekivati pri raspolovljenju doze AG-EE 388 ZW. (b) Considering the achieved reduction in blood sugar, significantly lower plasma levels of AG-EE 623 ZW occur than would be expected when the dose of AG-EE 388 ZW is halved.
(c) Učinak sniženja šećera nastaje brže poslije davanja AG-EE 623 ZW, nego poslije davanja AG-EE 388 ZW. (c) The sugar-lowering effect occurs faster after the administration of AG-EE 623 ZW than after the administration of AG-EE 388 ZW.
Eklatantna razlika između oba enantiomera postoji u tome, da se učinkoviti entaniomer, AG-EE 623 ZW, usprkos relativno dugotrajnog učinka, iznenađujuće bitno brže eliminira nego neučinkoviti enantiomer, AG-EE 624 ZW, kao što pokazuju sl. 1 i 2. Poslije davanja racemata neučinkoviti enantiomer, AG-EE 624 ZW, je dakle prisutan ne samo kao nepotreban balast u jednako visokim koncentracijama plazme kao učinkoviti enantiomer, AG-EE 623 ZW, ali u neočekivano višim maksimalnim i trajnim razinama. Ovo se primjerice odražava pri aplikaciji tablete s 2 mg AG-EE 388 ZW, odnosno tablete s 1 mg AG-ee 623 ZW pri 12 odnosno 6 pokusnih osoba tako, da su maksimalne koncentracije 84 ± 25 odnosno 28 ± 18 ng/ml kao i koncentracije poslije 4 sata 19 ± 8 odnosno 0,7 ± 1,0 ng/ml, poslije 5 sati 13 ± 6 odnosno 0,3 ± 0,7 ng/ml i poslije 6 sati 10 ± 6 odnosno 0,3 ± 0,7 ng/ml. The striking difference between both enantiomers is that the effective enantiomer, AG-EE 623 ZW, despite its relatively long-lasting effect, is surprisingly eliminated much faster than the ineffective enantiomer, AG-EE 624 ZW, as shown in Fig. 1 and 2. After administration the racemate's ineffective enantiomer, AG-EE 624 ZW, is therefore present not only as an unnecessary ballast in equally high plasma concentrations as the effective enantiomer, AG-EE 623 ZW, but in unexpectedly higher maximal and sustained levels. This is reflected, for example, in the application of tablets with 2 mg of AG-EE 388 ZW, i.e. tablets with 1 mg of AG-ee 623 ZW in 12 and 6 subjects, respectively, so that the maximum concentrations are 84 ± 25 and 28 ± 18 ng/ml, as well as concentrations after 4 hours 19 ± 8 or 0.7 ± 1.0 ng/ml, after 5 hours 13 ± 6 or 0.3 ± 0.7 ng/ml and after 6 hours 10 ± 6 or 0.3 ± 0, 7 ng/ml.
Iznenađujuće brzo uspostavljanje sniženja krvnog šećera s AG-EE 623 ZW u usporedbi s AG-EE 388 ZW je za dijabetičare posebno povoljna, jer brzo uspostavljanje ima za posljedicu optimalnu kontrolu bolesti. The surprisingly rapid onset of blood sugar lowering with AG-EE 623 ZW compared to AG-EE 388 ZW is particularly beneficial for diabetics, as the rapid onset results in optimal disease control.
U usporedbi s aplikacijom AG-EE 388 ZW postoji dakle iznenađujuća prednost aplikacije AG-EE 623 ZW u tome, da se izbjegne da velika i dugotrajna količina tvari nepotrebno opterećuje organizam, što je kod dugotrajne terapije, kao kod terapije Diabetis Mellitus, od velikog značenja. Compared to the AG-EE 388 ZW application, there is therefore a surprising advantage of the AG-EE 623 ZW application in that it avoids that a large and long-term amount of substance unnecessarily burdens the organism, which is of great importance in long-term therapy, such as in the treatment of Diabetes Mellitus .
Iz humanih je proučavanja vidljivo, da novi (S)-enantiomer, naime (S)-(+)-2-etoksi-4-[N-[1-(2-piperidino-fenil)-3-metil-1-butil]aminokarbonilmetil]-benzojeva kiselina, kao nosač učinkovitosti sniženja krvnog šećera zbog svoje iznenađujuće i na osnovi relativno dugotrajnog učinka nepredvidljive brze eliminacije iz krvi u usporedbi s AG-EE 388 ZW ima bolja svojstva, koja daleko prelaze "normalnu prednost" jednog enantiomera u usporedbi s njegovim racematom, naime prednost raspolovljanja doze. Human studies show that the new (S)-enantiomer, namely (S)-(+)-2-ethoxy-4-[N-[1-(2-piperidino-phenyl)-3-methyl-1-butyl ]aminocarbonylmethyl]-benzoic acid, as a carrier of blood sugar lowering efficiency due to its surprising and relatively long-term effect of unpredictable rapid elimination from the blood compared to AG-EE 388 ZW has better properties, which far exceed the "normal advantage" of one enantiomer in comparison with its racemate, namely the advantage of halving the dose.
Predmet predloženog izuma je dakle nova (S)-(+)-2-etoksi-4-[N-[1-(2-piperidino-fenil)-3-metil-1-butil]amino karbonilmetil]-benzojeva kiselina odnosno (S)-(+)-2-etoksi-4-[N-[1-(2-piperidino-fenil)-3-metil-1-butil ]amino karbonil metil]-benzojeva kiselina, koja je u biti optičko čista, npr. optičke čistoće barem ee = 95 %, ponajprije 98 do 100 %, njene fiziološko prihvatljive soli s anorganskim ili organskim kiselinama ili bazama, lijekovi, koji sadrže taj spoj odnosno njegove fiziološko prihvatljive soli i postupci za njezinu pripravu. The object of the proposed invention is therefore a new (S)-(+)-2-ethoxy-4-[N-[1-(2-piperidino-phenyl)-3-methyl-1-butyl]amino carbonylmethyl]-benzoic acid, or ( S)-(+)-2-ethoxy-4-[N-[1-(2-piperidino-phenyl)-3-methyl-1-butyl]amino carbonyl methyl]-benzoic acid, which is essentially optically pure, eg optical purity of at least ee = 95%, preferably 98 to 100%, its physiologically acceptable salts with inorganic or organic acids or bases, medicines containing that compound or its physiologically acceptable salts and procedures for its preparation.
U smislu izuma novi spoj dobivamo prema slijedećim postupcima: In terms of the invention, the new compound is obtained according to the following procedures:
a) Kemijska pretvorba (S)-amina formule a) Chemical transformation of (S)-amine of the formula
[image] [image]
s karboksilnom kiselinom opće formule with a carboxylic acid of the general formula
[image] [image]
U kojoj predstavlja In which he represents
W karboksi skupinu ili sa zaštitnim ostatkom zaštićenu karboksi skupinu, ili s njenim, u datom primjeru u reakcijskoj smjesi priređenim reakcijski sposobnim derivatom prema potrebi slijedi otcijepljenje zaštitnog ostatka. W carboxy group or a carboxy group protected with a protective residue, or with it, in the given example in the reaction mixture prepared by a reactive derivative is followed by cleavage of the protective residue as necessary.
Kao reakcijski sposobni derivati spoja opće formule II dolaze u obzir npr. njegovi esteri, kao metil-, etil- ili benzilester, njegovi tioesteri, kao metiltio- ili etiltioester, njegovi halogenidi, kao kiselinski klorid, njegovi anhidridi ili imidazolidi. As reactive derivatives of the compound of general formula II, for example, its esters, such as methyl-, ethyl- or benzyl ester, its thioesters, such as methylthio- or ethylthioester, its halides, such as acid chloride, its anhydrides or imidazolides, come into consideration.
Kemijsku pretvorbu svrhishodno izvodimo u otapalu, kao metilenkloridu, kloroformu, tetraklorugljiku, eteru, tetrahidrofuranu, dioksanu, benzolu, toluolu, acetonitrilu ili dimetilformamidu, u datom primjeru u prisutnosti sredstva koje aktivira kiselinu, ili sredstva za oduzimanje vode, npr. u prisutnosti etilestera klormravlje kiseline, izobutilestera klormravlje kiseline, tionilklorida, fosforova triklorida, fosforova pentoksida/ N,N'-diklorheksilkarbodiimida, N,N'-diklorheksilkarbodiimida/N-hidroksisukcinimida, N'N' -karbonildiimidazola ili N,N'-tionildiimidazola ili trifenil fosfina/tetraklorugljika/ ili sredstva, koje aktivira amino skupinu, npr. fosforova triklorida i u datom primjeru u prisutnosti anorganske baze, kao natrijeva karbonata ili tercijarne organske baze, kao trietilamina ili piridina, koji mogu istovremeno služiti kao otapala, pri temperaturama između -25 i 250°C, ponajprije pri temperaturama između -10°C i vrelišta uporabljenog otapala. Kemijsku pretvorbu možemo izvoditi također bez otapala, dalje možemo i pri pretvorbi nastalu vodu odvojiti azeotropnom destilacijom, npr. zagrijavanjem s toluenom na separatoru vode, ili dodatkom sredstva za sušenje, kao magnezijeva sulfata ili molekularnoga sita. The chemical conversion is expediently carried out in a solvent, such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, in the given example in the presence of an agent that activates the acid, or an agent for removing water, e.g. in the presence of ethyl chloride formate acid, chloroformic acid isobutyl ester, thionyl chloride, phosphorus trichloride, phosphorus pentoxide/ N,N'-dichlorohexylcarbodiimide, N,N'-dichlorohexylcarbodiimide/N-hydroxysuccinimide, N'N'-carbonyldiimidazole or N,N'-thiondiimidazole or triphenyl phosphine/carbon tetrachloride / or means that activate the amino group, for example phosphorus trichloride and in the given example in the presence of an inorganic base, such as sodium carbonate or a tertiary organic base, such as triethylamine or pyridine, which can simultaneously serve as solvents, at temperatures between -25 and 250°C , preferably at temperatures between -10°C and the boiling point of the solvent used. The chemical conversion can also be carried out without a solvent, and we can also separate the water produced during the conversion by azeotropic distillation, for example by heating it with toluene on a water separator, or by adding a drying agent, such as magnesium sulfate or molecular sieves.
Prema potrebi zatim izvodimo otcijepljenje zaštitnog ostatka ponajprije hidrolitički, svrhishodno bilo u prisutnosti kiseline, kao solne kiseline, sumporne kiseline, fosforne kiseline, trifluoroctene kiseline ili trikloroctene kiseline, ili u prisutnosti baze, kao natrijeva hidroksida ili kalijeva hidroksida, u odgovarajućem otapalu, kao vodi, metanolu, metanolu/vodi, etanolu/vodi, vodi/izopropanolu ili vodi/dioksanu, pri temperaturama između -10 i 120°C, npr. pri temperaturama između sobne i vrelišta reakcijske smjese. If necessary, we then carry out the separation of the protective residue primarily hydrolytically, expediently either in the presence of an acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or trichloroacetic acid, or in the presence of a base, such as sodium hydroxide or potassium hydroxide, in a suitable solvent, such as water , methanol, methanol/water, ethanol/water, water/isopropanol or water/dioxane, at temperatures between -10 and 120°C, for example at temperatures between room temperature and the boiling point of the reaction mixture.
Kao zaštitni ostatak uporabljeni terc-butilni ostatak možemo također termički otcijepiti, u datom primjeru u inertnom otapalu, kao metilenkloridu, kloroformu, benzolu, toluolu, tetrahidrofuranu, dioksanu ili ledenoj octenoj kiselini, i ponajprije u prisutnosti jake kiseline, kao trifluoroctene kiseline, bromovodika, p-toluensulfonske kiseline, sumporne kiseline, fosforne kiseline ili polifosforne kiseline. The tert-butyl residue used as a protective residue can also be cleaved thermally, in the given example in an inert solvent, such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran, dioxane or glacial acetic acid, and preferably in the presence of a strong acid, such as trifluoroacetic acid, hydrogen bromide, p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid.
Dalje možemo kao zaštitni ostatak uporabljeni benzilni ostatak otcijepiti i hidrogenolitički u prisutnosti katalizatora za hidriranje, kao paladija/ugljena, u prikladnom otapalu, kao metanolu, etanolu, etanolu/vodi, ledenoj octenoj kiselini, etilesteru octene kiseline, dioksanu ili dimetilformamidu. Furthermore, the benzyl residue used as a protective residue can also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst, such as palladium/charcoal, in a suitable solvent, such as methanol, ethanol, ethanol/water, glacial acetic acid, acetic acid ethyl ester, dioxane or dimethylformamide.
b) Cijepanje (S)-spoja opće formule b) Cleavage of the (S)-compound of the general formula
[image] [image]
u kojoj predstavlja in which it represents
A hidrolizom, termolizom ili hidrogenolizom u karboksi skupinu prevodljivu skupinu. And by hydrolysis, thermolysis or hydrogenolysis into a carboxy group a convertible group.
Kao skupine koje se daju hidrolizirati u obzir dolaze npr. funkcionalni derivati karboksi skupine, kao njeni nesupstituirani ili supstituirani amidi, esteri, tioesteri, ortoesteri, iminoeteri, amidini ili anhidridi, nitrilna skupina, tetrazolilna skupina, u datom primjeru supstituirana 1,3-oksazol-2-ilna ili 1,3-oksazolin-2-ilna skupina, i Examples of groups that can be hydrolyzed include functional derivatives of the carboxy group, such as its unsubstituted or substituted amides, esters, thioesters, orthoesters, iminoethers, amidines or anhydrides, nitrile group, tetrazolyl group, in the given example substituted 1,3-oxazole -2-yl or 1,3-oxazolin-2-yl group, i
kao termolitički otcijepljive skupine npr. esteri s tercijarnim alkoholima, npr. terc-butilester, i as thermolytically cleavable groups, e.g. esters with tertiary alcohols, e.g. tert-butyl ester, and
kao hidrogenolitički otcijepljive skupine npr. aralkilne skupine, npr. benzilna skupina. as hydrogenolytically cleavable groups, e.g. aralkyl groups, e.g. benzyl group.
Hidrolizu smisleno izvedemo bilo u prisutnosti kiseline, kao solne kiseline, sulfatne kiseline, fosforne kiseline, trifluoroctene kiseline ili trikloroctene kiseline, ili u prisutnosti baze, kao natrijeva hidroksida ili kalijeva hidroksida, u prikladnom otapalu, kao vodi, vodi/metanolu, vodi/etanolu, vodi/izopropanolu ili vodi/dioksanu, pri temperaturama između -10 i 120°C, npr. pri temperaturama između sobne temperature i vrelišta reakcijske smjese. We meaningfully carry out the hydrolysis either in the presence of an acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or trichloroacetic acid, or in the presence of a base, such as sodium hydroxide or potassium hydroxide, in a suitable solvent, such as water, water/methanol, water/ethanol , water/isopropanol or water/dioxane, at temperatures between -10 and 120°C, eg at temperatures between room temperature and the boiling point of the reaction mixture.
Ako A znači u spoju opće formule III nitrilnu ili aminokarbonilnu skupinu ove skupine možemo prevesti pomoću 100 % fosforne kiseline u karboksi skupinu pri temperaturama između 100 i 180°C, ponajprije pri temperaturama između 120 i 160°C, ili također s nitritom, npr. natrijevim nitritom, u prisutnosti kiseline, kao sumporne kiseline, pri čemu ovu svrhishodno istovremeno uporabimo kao otapalo, pri temperaturama između 0 i 50°C. If A means in the compound of the general formula III, the nitrile or aminocarbonyl group of this group can be converted using 100% phosphoric acid into a carboxy group at temperatures between 100 and 180°C, preferably at temperatures between 120 and 160°C, or also with nitrite, e.g. with sodium nitrite, in the presence of an acid, such as sulfuric acid, and this is expediently used as a solvent at the same time, at temperatures between 0 and 50°C.
Ako A znači u spoju opće formule III npr. terc-butiloksikarbonilnu skupinu, terc-butilnu skupinu možemo također termički otcijepiti, u datom primjeru u inertnom otapalu, kao metilenkloridu, kloroformu, benzolu, toluolu, tetrahidrofuranu, dioksanu ili ledenoj octenoj kiselini, i ponajprije u prisutnosti jake kiseline kao trifluoroctene kiseline, bromovodika, p-toluensulfonske kiseline, sumporne kiseline, fosforne kiseline ili polifosforne kiseline, pri temperaturama između 0 i 100°C, ponajprije pri temperaturama između 20°C i vrelišta uporabljenog otapala. If A means in the compound of the general formula III, for example, a tert-butyloxycarbonyl group, the tert-butyl group can also be cleaved off thermally, in the given example in an inert solvent, such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran, dioxane or glacial acetic acid, and preferably in the presence of a strong acid such as trifluoroacetic acid, hydrogen bromide, p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid, at temperatures between 0 and 100°C, preferably at temperatures between 20°C and the boiling point of the solvent used.
Ako A u spoju opće formule III znači npr. benziloksikarbonilnu skupinu, benzilnu skupinu možemo otcijepiti i hidrogenolitički u prisutnosti katalizatora za hidriranje, kao paladija/ugljena, u prikladnom otapalu, kao metanolu, etanolu, metanolu/vodi, ledenoj octenoj kiselini, etilesteru octene kiseline, dioksanu ili dimetilformamidu, ponajprije pri temperaturama između 0 i 50°C, npr. pri sobnoj temperaturi, i tlaku vodika od 1 do 5 bara. If A in the compound of the general formula III means, for example, a benzyloxycarbonyl group, the benzyl group can also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst, such as palladium/charcoal, in a suitable solvent, such as methanol, ethanol, methanol/water, glacial acetic acid, acetic acid ethyl ester , dioxane or dimethylformamide, preferably at temperatures between 0 and 50°C, for example at room temperature, and a hydrogen pressure of 1 to 5 bar.
c) Pretvorba (S)-spoja opće formule c) Conversion of the (S)-compound of the general formula
[image] [image]
u kojoj znači in which means
W karboksi skupinu ili alkoksikarbonilnu skupinu zajedno s 2 do 5 ugljikova atoma, pri čemu može biti alkilni dio alkoksi skupine supstituiran s fenilnom skupinom, sa spojem opće formule W a carboxy group or an alkoxycarbonyl group together with 2 to 5 carbon atoms, whereby the alkyl part of the alkoxy group may be substituted with a phenyl group, with a compound of the general formula
[image] [image]
u kojoj predstavlja in which it represents
Z nukleofilnu izmjenljivu skupinu, kao atom halogena, sulfoniloksi skupinu ili također zajedno sa susjednim atomom vodika diazo skupinu, i prema potrebi slijedi hidroliza ili hidrogenoliza. With a nucleophilic exchangeable group, such as a halogen atom, a sulfonyloxy group or also together with an adjacent hydrogen atom a diazo group, followed by hydrolysis or hydrogenolysis as required.
Pretvorbu izvedemo smisleno s odgovarajućim halogenidom, esterom sulfonske kiseline ili diesterom sulfatne kiseline, npr. s etilbromidom, etiljodidom, dietilsulfatom, etilesterom p-toluensulfonske kiseline ili etilesterom metansulfonske kiseline, ili s diazoetanom, u datom primjeru u prisutnosti baze, kao natrijeva hidrida, kalijeva karbonata, natrijeva hidroksida, kalijeva terc-butilata ili trietilamina, ponajprije u pogodnom otapalu, kao acetonu, dietileteru, tetrahidrofuranu, dioksanu, piridinu ili dimetilformamidu, pri temperaturama između 0 i 100°C, ponajprije pri temperaturama između 20 i 50°C. The conversion is meaningfully carried out with the appropriate halide, sulfonic acid ester or sulfuric acid diester, for example with ethyl bromide, ethyl iodide, diethyl sulfate, ethyl ester of p-toluenesulfonic acid or ethyl ester of methanesulfonic acid, or with diazoethane, in the given example in the presence of a base, such as sodium hydride, potassium carbonate, sodium hydroxide, potassium tert-butylate or triethylamine, preferably in a suitable solvent, such as acetone, diethyl ether, tetrahydrofuran, dioxane, pyridine or dimethylformamide, at temperatures between 0 and 100°C, preferably at temperatures between 20 and 50°C.
Ako W' u spoju opće formule IV znači karboksi skupinu, možemo ovu prevesti u odgovarajući esterski spoj. If W' in the compound of the general formula IV means a carboxy group, we can translate this into the corresponding ester compound.
Prema potrebi izvedemo slijedeću hidrolizu bilo u prisutnosti kiseline, kao solne kiseline, sulfatne kiseline, fosforne kiseline, ili u prisutnosti baze, kao natrijeva hidroksida ili kalijeva hidroksida, u prikladnom otapalu, kao vodi, metanolu, metanolu/vodi, etanolu, etanolu/vodi, vodi/izopropanolu ili vodi/dioksanu, pri temperaturama između -10 i 120°C, npr. pri temperaturama između sobne temperature i vrelišta reakcijske smjese, ili If necessary, we carry out the following hydrolysis either in the presence of an acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, or in the presence of a base, such as sodium hydroxide or potassium hydroxide, in a suitable solvent, such as water, methanol, methanol/water, ethanol, ethanol/water , water/isopropanol or water/dioxane, at temperatures between -10 and 120°C, e.g. at temperatures between room temperature and the boiling point of the reaction mixture, or
slijedeću hidrogenolizu u prisutnosti katalizatora za hidriranje, kao paladija/ugljena, u prikladnom otapalu, kao metanolu, etanolu, etanolu/vodi, ledenoj octenoj kiselini, etilesteru octene kiseline, dioksanu ili dimetilformamidu, pri tlaku vodika od 1 do 10 bara. subsequent hydrogenolysis in the presence of a hydrogenation catalyst, such as palladium/charcoal, in a suitable solvent, such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, at a hydrogen pressure of 1 to 10 bar.
d) Enantioselektivna redukcija spoja opće formule d) Enantioselective reduction of a compound of the general formula
[image] [image]
u kojoj predstavlja in which it represents
W' karboksi skupinu ili alkoksikarbonilnu skupinu zajedno sa 2 do 5 ugljikova atoma, pri čemu alkilni dio alkoksi skupine može biti supstituiran s fenilnom skupinom, W' a carboxy group or an alkoxycarbonyl group together with 2 to 5 carbon atoms, whereby the alkyl part of the alkoxy group can be substituted with a phenyl group,
Y skupinu formule Y group of the formula
[image] [image]
i prema potrebi slijedi hidroliza. and hydrolysis follows if necessary.
Redukciju izvedemo ponajprije s vodikom u prisutnosti pogodnog kiralnog katalizatora za hidriranje u prikladnom otapalu, kao metanolu, etanolu, izopropanolu, etilacetatu, dioksanu, tetrahidrofuranu, metanolu/tetrahidrofuranu, metanolu/metilenkloridu, etanolu/metilenkloridu ili izopropanolu/metilenkloridu, pri temperaturama između 0 i 100°C, ponajprije pri temperaturama između 20 i 50°C, i tlaku vodika između 1 i 1000 bara, ponajprije između 5 i 100 bara, i smisleno uz dodatak 0,1 do 5 %, ponajprije 0,3 do 1 %, titanova(IV)-tetraizopropilata, i ponajprije uz isključenje kisika, koji se nalazi u zraku. Ponajprije izvedemo redukciju sa (Z)-oblikom spoja opće formule VI. The reduction is primarily carried out with hydrogen in the presence of a suitable chiral catalyst for hydrogenation in a suitable solvent, such as methanol, ethanol, isopropanol, ethyl acetate, dioxane, tetrahydrofuran, methanol/tetrahydrofuran, methanol/methylene chloride, ethanol/methylene chloride or isopropanol/methylene chloride, at temperatures between 0 and 100°C, preferably at temperatures between 20 and 50°C, and hydrogen pressure between 1 and 1000 bar, preferably between 5 and 100 bar, and meaningfully with the addition of 0.1 to 5%, preferably 0.3 to 1%, of titanium (IV)-tetraisopropylate, and primarily with the exclusion of oxygen, which is in the air. First of all, we perform the reduction with the (Z)-form of the compound of the general formula VI.
Kao kiralni hidrirni katalizatori u obzir dolaze odgovarajući metalni kompleksi s ligandima, kao Ru (OCO-CH3) 2[ (S) -BINAP], Ru2Cl4[(S)-BINAP]2 x N(C2H5)3, Rh[ (S)-BINAP-NBD]ClO4 ili Rh[ (-) -NORPHOS-COD]BF4 . Suitable metal complexes with ligands, such as Ru (OCO-CH3) 2[ (S)-BINAP], Ru2Cl4[(S)-BINAP]2 x N(C2H5)3, Rh[ (S) -BINAP-NBD]ClO4 or Rh[(-)-NORPHOS-COD]BF4.
Pri katalitičkom hidriranju možemo benziloksikarbonilnu skupinu istovremeno sureducirati i prevesti u karboksi skupinu. During catalytic hydrogenation, the benzyloxycarbonyl group can be co-reduced at the same time and converted into a carboxy group.
Prema potrebi izvedemo zatim hidrolizu bilo u prisutnosti kiseline, kao solne kiseline, sulfatne kiseline, fosforne kiseline, trifluoroctene kiseline ili trikloroctene kiseline, ili u prisutnosti baze, kao natrijeva hidroksida ili kalijeva hidroksida, u prikladnom otapalu, kao vodi, metanolu, metanolu/vodi, etanolu, etanolu/vodi, vodi/izopropanolu ili vodi/dioksanu, pri temperaturama između -10 i 120°C, npr. pri temperaturama. između sobne temperature i vrelišta reakcijske smjese. If necessary, we then carry out hydrolysis either in the presence of an acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or trichloroacetic acid, or in the presence of a base, such as sodium hydroxide or potassium hydroxide, in a suitable solvent, such as water, methanol, methanol/water , ethanol, ethanol/water, water/isopropanol or water/dioxane, at temperatures between -10 and 120°C, eg at temps. between room temperature and the boiling point of the reaction mixture.
e) Oksidacija (S)-spoja opće formule e) Oxidation of the (S)-compound of the general formula
[image] [image]
u kojoj predstavlja in which it represents
W" u karboksi skupinu oksidacijom prevedljivu skupinu. W" to the carboxy group by oxidizing the translatable group.
Kao skupina koja se može oksidirati, u obzir dolazi npr. formilna skupina i njezini acetali, hidroksimetilna skupina i njeni eteri, nesupstituirana ili supstituirana acilna skupina, kao acetilna, kloracetilna, propionilna, malonska kiselina-(1)-ilna skupina ili malonester-(1)-ilna skupina. As a group that can be oxidized, for example a formyl group and its acetals, a hydroxymethyl group and its ethers, an unsubstituted or substituted acyl group, such as an acetyl, chloroacetyl, propionyl, malonic acid-(1)-yl group or a malonester-( 1)-yl group.
Pretvorbu izvedemo s oksidacijskim sredstvom u pogodnom otapalu, kao vodi, ledenoj octenoj kiselini, metilenkloridu, dioksanu, glikoldimetileteru, pri temperaturama između 0 i 100°C, smisleno pri temperaturama između 20 i 50°C. Pretvorbu ponajprije izvedemo sa srebrnim oksidom/natrijevom lužinom, manganovim dioksidom/acetonom ili metilenkloridom, vodikovim peroksidom/natrijevom lužinom, bromom ili klorom/natrijevom ili kalijevom lužinom, kromovim trioksidom/piridinom ili piridinijevim klorkromatom. The conversion is carried out with an oxidizing agent in a suitable solvent, such as water, glacial acetic acid, methylene chloride, dioxane, glycoldimethylether, at temperatures between 0 and 100°C, meaningfully at temperatures between 20 and 50°C. The conversion is primarily carried out with silver oxide/sodium alkali, manganese dioxide/acetone or methylene chloride, hydrogen peroxide/sodium alkali, bromine or chlorine/sodium or potassium alkali, chromium trioxide/pyridine or pyridinium chlorochromate.
f) Odvajanje smjese, koja se sastoji od proizvoljne količine (S)-enantiomera opće formule f) Separation of the mixture, which consists of an arbitrary amount of (S)-enantiomers of the general formula
[image] [image]
i proizvoljne količine (R)-enantiomera opće formule and arbitrary amounts of the (R)-enantiomer of the general formula
[image] [image]
u kojima znači in which it means
W' karboksi skupinu ili alkoksikarbonilnu skupinu zajedno s 2 do 5 ugljikova atoma, pri čemu može biti alkilni dio alkoksi skupine supstituiran s fenilnom skupinom, ponajprije smjese 50/50, preko njenih dijasteromernih adukata, kompleksa ili soli, i prema potrebi slijedi hidroliza ili hidrogenoliza. W' is a carboxy group or an alkoxycarbonyl group together with 2 to 5 carbon atoms, whereby the alkyl part of the alkoxy group can be substituted with a phenyl group, preferably a 50/50 mixture, via its diastereomeric adducts, complexes or salts, followed by hydrolysis or hydrogenolysis if necessary .
Odvajanje izvedemo ponajprije pomoću kolonske ili HPL-kromatografije s tvorbom dijastereomernih adukata ili kompleksa na kiralnoj fazi. The separation is primarily performed using column or HPL chromatography with the formation of diastereomeric adducts or complexes on the chiral phase.
Prema potrebi izvedemo zatim hidrolizu bilo u prisutnosti kiseline, kao solne kiseline, sulfatne kiseline, fosforne kiseline, trifluoroctene kiseline ili trikloroctene kiseline, ili u prisutnosti baze, kao natrijeva hidroksida ili kalijeva hidroksida, u prikladnom otapalu, kao vodi, metanolu, metanolu/vodi, etanolu, etanolu/vodi, vodi/izopropanolu ili vodi/dioksanu, pri temperaturama između -10 i 120°C, npr. pri temperaturama između sobne temperature i vrelišta reakcijske smjese, ili If necessary, we then carry out hydrolysis either in the presence of an acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or trichloroacetic acid, or in the presence of a base, such as sodium hydroxide or potassium hydroxide, in a suitable solvent, such as water, methanol, methanol/water , ethanol, ethanol/water, water/isopropanol or water/dioxane, at temperatures between -10 and 120°C, e.g. at temperatures between room temperature and the boiling point of the reaction mixture, or
zatim hidrogenolizu u prisutnosti katalizatora za hidriranje, kao paladija/ugljena, u prikladnom otapalu, kao metanolu, etanolu, etanolu/vodi, ledenoj octenoj kiselini, etilesteru octene kiseline, dioksanu ili dimetilformamidu, pri tlaku vodika od 1 do 10 bara. then hydrogenolysis in the presence of a hydrogenation catalyst, such as palladium/charcoal, in a suitable solvent, such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, at a hydrogen pressure of 1 to 10 bar.
Tako u smislu izuma dobiveni (S)-enantiomer s optičkom čistoćom svrhishodno barem 90 % može se frakcionom kristalizacijom prevesti u (S)-enantiomer s optičkom čistoćom barem 95 %, ponajprije 98 do 100 %. Thus, according to the invention, the obtained (S)-enantiomer with an optical purity of at least 90% can be converted by fractional crystallization into an (S)-enantiomer with an optical purity of at least 95%, preferably 98 to 100%.
Jednako vrijedi za (S)-spojeve s formulama III/ IV i VII u smislu izuma, posebno za njihove estere. The same applies to the (S)-compounds with the formulas III/IV and VII within the meaning of the invention, especially for their esters.
Tako u smislu izuma dobiveni (S)-enantiomer se može prevesti u svoje soli, posebno za farmaceutsku uporabu u svoje fiziološko prihvatljive soli s anorganskim ili organskim kiselinama ili također bazama. Kao kiseline dolaze kod toga u obzir npr. solna kiseline, bromidna kiselina, sumporna kiseline, fosforna kiseline, mliječna kiselina, limunska kiselina, vinska kiselina, jantarna kiselina, maleinska kiselina ili fumarna kiselina, i kao baze natrijev hidroksid, kalijev hidroksid, kalcijev hidroksid, cikloheksilamin, etanolamin, dietanolamin, trietanolamin, etilendiamin ili lizin. Thus, according to the invention, the obtained (S)-enantiomer can be converted into its salts, especially for pharmaceutical use into its physiologically acceptable salts with inorganic or organic acids or also bases. As acids, for example, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid or fumaric acid, and as bases sodium hydroxide, potassium hydroxide, calcium hydroxide come into consideration. , cyclohexylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine or lysine.
Spojevi s formulama 1 do IX, uporabljeni kao polazne tvari, djelomično su poznati iz literature, odnosno, dobivamo ih prema poznatim postupcima. Compounds with formulas 1 to IX, used as starting substances, are partially known from the literature, that is, they are obtained according to known procedures.
(S)-amin formule I možemo dobiti iz odgovarajućeg racemičnog amina The (S)-amine of formula I can be obtained from the corresponding racemic amine
s cijepanjem racemata, npr. frakcionom kristalizacijom dijastereomernih soli s prikladnim optičko aktivnim kiselinama, ponajprije s N-acil-L-glutaminskom kiselinom, i prema potrebi prekristalizacijom, kao i zatim razgradnjom soli, with resolution of the racemate, e.g. fractional crystallization of diastereomeric salts with suitable optically active acids, preferably with N-acyl-L-glutamic acid, and if necessary recrystallization, as well as subsequent decomposition of the salt,
s kolonskom ili HPL-kromatografijom na kiralnim fazama, u datom primjeru u obliku acilnog derivata, with column or HPL-chromatography on chiral phases, in the given example in the form of an acyl derivative,
ili s tvorbom dijastereomernih spojeva, njihovim odvajanjem i zatim cijepanjem. or with the formation of diastereomeric compounds, their separation and then cleavage.
Nadalje možemo (S)-amin dobiti s visokom enantioiaernom čistoćom Furthermore, (S)-amine can be obtained with high enantioiaer purity
s enantioselektivnom redukcijom pomoću vodika u prisutnosti pogodnog kiralnog katalizatora za hidriranje iz odgovarajućeg N-acil-ketimina odnosno enamida, smisleno uz dodatak 0,1 do 5 % titanova tetraizopropilata, i u datom primjeru zatim otcjepljenje acilnog ostatka, kao formilnog ili acetilnog ostatka, with enantioselective reduction by means of hydrogen in the presence of a suitable chiral catalyst for hydrogenation from the corresponding N-acyl-ketimine or enamide, meaningfully with the addition of 0.1 to 5% titanium tetraisopropylate, and in the given example then splitting off the acyl residue, as a formyl or acetyl residue,
s dijasteroselektvnom redukcijom odgovarajućeg, na atomu dušika kiralno supstituiranoga ketimina ili hidrazina pomoću vodika u prisutnosti prikladnog katalizatora za hidriranje, svrhishodno uz dodatak 0,1 do 5 % titanova tetraizopropilata, i u datom primjeru slijedi otcjepljenje kiralnog pomoćnog ostatka, npr. (S)-1-fenetilnog ostatka, s katalitičkom hidrogenolizom, ili with the diastereoselective reduction of the corresponding, chirally substituted ketimine or hydrazine on the nitrogen atom by hydrogen in the presence of a suitable hydrogenation catalyst, expediently with the addition of 0.1 to 5% titanium tetraisopropylate, and in the given example followed by cleavage of the chiral auxiliary residue, e.g. (S)-1 -phenethyl residue, with catalytic hydrogenolysis, or
s dijastereoselektivnom adicijom odgovarajućeg organometalnog spoja, ponajprije Grignarovog ili litijevog spoja, na odgovarajući, na atomu dušika kiralno supstituiran aldimin, u datom primjeru uz dodatak 0,1 do 10 % titanova tetraizopropilata, slijedi hidroliza i u datom primjeru slijedi odvajanje dobivenih dijastereomera i zatim otcjepljenje kiralnog pomoćnog ostatka, npr. (R)-1-fenetilnog ostatka, s katalitičkom hidrogenolizom, with the diastereoselective addition of a suitable organometallic compound, preferably a Grignard or lithium compound, to a suitable aldimine chirally substituted on the nitrogen atom, in the given example with the addition of 0.1 to 10% titanium tetraisopropylate, followed by hydrolysis and in the given example followed by the separation of the obtained diastereomers and then the separation of the chiral of an auxiliary residue, e.g. (R)-1-phenethyl residue, with catalytic hydrogenolysis,
i prema potrebi s tvorbom soli s prikladnim optičko aktivnim kiselinama, ponajprije s N-acetil-L-glutaminskom kiselinom i prema potrebi jedan puta ili više puta prekristalizacijom, kao i zatim razgradnjom soli. and if necessary with the formation of salts with suitable optically active acids, preferably with N-acetyl-L-glutamic acid and if necessary one or more times by recrystallization, as well as then decomposition of the salt.
Spojeve s općim formulama III, IV i VII, upotrebljene kao polazne tvari, dobivamo pretvorbom (S)-amina 1 s odgovarajućom karboksilnom kiselinom odnosno njezinim reaktivnim derivatima i u datom primjeru slijedi otcjepljenje upotrebljenog zaštitnog ostatka. Compounds with general formulas III, IV and VII, used as starting substances, are obtained by converting (S)-amine 1 with the appropriate carboxylic acid or its reactive derivatives, and in the given example, the used protective residue is removed.
Spoj opće formule VI, upotrebljen kao polazna tvar, dobivamo s aciliranjem odgovarajućeg imino spoja ili njegovih organometalnih kompleksa s odgovarajućom karboksilnom kiselinom ili njezinim reaktivnim derivatima zatim s možebitnim cijepanjem esterske skupine. The compound of the general formula VI, used as a starting substance, is obtained by acylation of the corresponding imino compound or its organometallic complexes with a corresponding carboxylic acid or its reactive derivatives, followed by possible cleavage of the ester group.
Novi (S)-enantiomer je praktično neotrovan; npr. poslije jedne aplikacije 1000 mg/kg p.o. (suspenzija u 1 %-ni metilcelulozi) svaki puta pet mužjaka i pet ženaka štakora ni jedna životinja nije uginula u naknadnom vremenu promatranja 14 dana. The new (S)-enantiomer is practically non-toxic; e.g. after one application of 1000 mg/kg p.o. (suspension in 1% methylcellulose) each time five male and five female rats and not one animal died in the subsequent observation time of 14 days.
Na osnovi svojih farmakoloških i farmakokinetičkih svojstava pripravljeni su u smislu izuma (S)-enantiomer AG-EE 623 ZW i njegove fiziološko prihvatljive soli prikladne za liječenje Diabetes mellitus. Za ovo se mogu AG-EE 623 ZW ili njegove fiziološko prihvatljive soli, u datom primjeru u kombinaciji s drugim učinkovitim tvarima, ugraditi u uobičajene galenske oblike pripravaka, kao tablete, dražeje, kapsule, praške, čepiće, suspenzije ili injekcijske otopine. Pojedinačna doza pritom za odraslog iznosi 0,1 do 20 mg, ponajprije 0,25 do 5 mg, naročito 0,25, 0,5, 1,0, 1,5, 2,0, 2,5, 3,0 ili 5,0 mg jedan, dva ili tri puta dnevno. On the basis of their pharmacological and pharmacokinetic properties, the (S)-enantiomer AG-EE 623 ZW and its physiologically acceptable salts suitable for the treatment of Diabetes mellitus are prepared according to the invention. For this, AG-EE 623 ZW or its physiologically acceptable salts, in the given example in combination with other effective substances, can be incorporated into the usual galenic forms of preparations, such as tablets, dragees, capsules, powders, suppositories, suspensions or injection solutions. The individual dose for an adult is 0.1 to 20 mg, preferably 0.25 to 5 mg, especially 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0 or 5.0 mg one, two or three times a day.
Dalji predmet predloženog izuma je novi (S)-amin formule I, koji predstavlja dragocijen međuprodukt za pripravu novog (S)-enantiomera, kao i njegove adicijske soli s anorganskim ili organskim kiselinama. A further object of the proposed invention is the new (S)-amine of formula I, which represents a valuable intermediate for the preparation of the new (S)-enantiomer, as well as its addition salts with inorganic or organic acids.
Dalji predmet predloženog izuma su novi spojevi s općim formulama III, IV i VII, koji predstavljaju dragocijene međuprodukte za pripravu novog (S)-enantiomera, kao i njegove adicijske soli s anorganskim ili organskim kiselinama. A further subject of the proposed invention are new compounds with general formulas III, IV and VII, which represent valuable intermediates for the preparation of the new (S)-enantiomer, as well as its addition salts with inorganic or organic acids.
Slijedeći primjeri pobliže objašnjavaju izum. The following examples explain the invention in more detail.
PRIMJER A EXAMPLE A
(S)-1-(2-piperidino-fenil)-3-metil-1-butilamin (S)-1-(2-piperidino-phenyl)-3-methyl-1-butylamine
Otopini 122 g (0,495 mola) racemičnog 1-(2-piperidino-fenil)-3-metil-1-butilamina u 1000 ml acetona uz miješanje dodajemo 93,7 g (0,495 mola) N-acetil-L-glutaminske kiseline. Zagrijemo na parnoj kupelji uz refluks i u obrocima dodajemo metanol (zajedno oko 80 ml), sve dok se ne dobije bistra otopina. Poslije hlađenja i stajanja preko noći pri sobnoj temperaturi, odsišemo dobivene kristale, isperemo 2-puta s po 200 ml hladnoga acetona (-15°C) i osušimo. Dobiveni produkt [98,9 g; tal. :163-166°C; [α]D20= +0,286° (c = 1 u metanolu)] prekristaliziramo iz 1000 ml acetona uz dodatak 200 ml metanola, pri čemu dobijemo (S)-1-(2-piperidino-fenil)-3-metil-1-butilaitlin kao adicijsku sol N-acetil-L-glutaminske kiseline. To a solution of 122 g (0.495 mol) of racemic 1-(2-piperidino-phenyl)-3-methyl-1-butylamine in 1000 ml of acetone, we add 93.7 g (0.495 mol) of N-acetyl-L-glutamic acid while stirring. Heat on a steam bath under reflux and add methanol in portions (about 80 ml in total) until a clear solution is obtained. After cooling and standing overnight at room temperature, the resulting crystals are sucked off, washed twice with 200 ml of cold acetone (-15°C) and dried. The product obtained [98.9 g; tal. :163-166°C; [α]D20= +0.286° (c = 1 in methanol)] is recrystallized from 1000 ml of acetone with the addition of 200 ml of methanol, thereby obtaining (S)-1-(2-piperidino-phenyl)-3-methyl-1- butylitlin as an addition salt of N-acetyl-L-glutamic acid.
Iskorištenje: 65,1 g (60,4 % teor.) Yield: 65.1 g (60.4 % of theory)
tal.: 168-171°C melting point: 168-171°C
[image] [image]
[α]D20= 0,357° (c = 1 u metanolu) [α]D20= 0.357° (c = 1 in methanol)
Slobodni amin dobijemo kao ulje s oslobađanjem npr. s otopinom natrijeva hidroksida ili amonijaka, ekstrakcijom, npr. s toluolom, eterom, etilacetatom ili metilenkloridom, kao i sa sušenjem, filtriranjem i uparivanjem ekstrakta u vakuumu. The free amine is obtained as an oil with release, for example, with sodium hydroxide or ammonia solution, extraction, for example, with toluene, ether, ethyl acetate or methylene chloride, as well as with drying, filtering and evaporation of the extract in a vacuum.
(S)-konfiguraciju amina dokažemo, kao što slijedi: We prove the (S)-configuration of the amine as follows:
Pretvorba amina s (S')-1-fenetilizocijanatom u eteru u odgovarajući derivat uree [tal.:183 do 184°C; [α]D20= -2,25° (c = 1 u metanolu)], uzgoj kristala iz etanola/vode (8/1) i zatim rentgenska strukturna analiza, koja daje (S,S')-konfiguraciju za derivat uree i s time (S)-konfiguraciju za uporabljeni amin. Conversion of the amine with (S')-1-phenethylisocyanate in ether to the corresponding urea derivative [mp: 183 to 184°C; [α]D20= -2.25° (c = 1 in methanol)], crystal growth from ethanol/water (8/1) and then X-ray structural analysis, which gives the (S,S')-configuration for the urea derivative and s thus (S)-configuration for the amine used.
Enantiomernu čistoću odredimo, kao što slijedi: We determine the enantiomeric purity as follows:
1. Acetiliranje uzorka amina s 1,3 ekvivalenta acetanhidrida u ledenoj octenoj kiselini preko noći pri 20°C. 1. Acetylation of the amine sample with 1.3 equivalents of acetic anhydride in glacial acetic acid overnight at 20°C.
2. Ispitivanje N-acetilnog derivata (tal. 128 do 132°C) s HPLC na kiralne-faze-HPLC-koloni s kiralnim gazama tvrtke Baker, pri kojoj je (S)-N-(3,5-dinitrobenzoil)-2-fenil-glicin kovalentno vezan na aminopropil-silikagel (veličina zrna: 5 µm, kuglasta, širina pora 6 nm, dužina kolone: 250 mm s unutarnjim promjerom 4,6 mm; eluirno sredstvo; n-heksan/izopropanol (100/5); brzina eluiranja: 2 ml/min; 2. Examination of the N-acetyl derivative (m.p. 128 to 132°C) by HPLC on a chiral phase HPLC column with chiral gases from the company Baker, in which (S)-N-(3,5-dinitrobenzoyl)-2 -phenyl-glycine covalently bound to aminopropyl-silica gel (grain size: 5 µm, spherical, pore width 6 nm, column length: 250 mm with an internal diameter of 4.6 mm; eluent; n-hexane/isopropanol (100/5) elution rate: 2 ml/min;
temperatura: 20°C; UV-detekcija pri 254 nm) . temperature: 20°C; UV-detection at 254 nm).
Ustan.: Peak 1(R); Peak 2(S) = 0,75 %: 99,25 %, Establishment: Peak 1(R); Peak 2(S) = 0.75%: 99.25%,
ee (enantiomeric excess) = 98,5 % (S). ee (enantiomeric excess) = 98.5 % (S).
Pomoću eterske otopine klorovodika možemo prevesti (S)-amin u njegov dihidroklorid-hidrat. Using an ethereal solution of hydrogen chloride, we can convert (S)-amine into its dihydrochloride hydrate.
[image] [α]D20= +26,1° (c = 1 u metanolu) [image] [α]D20= +26.1° (c = 1 in methanol)
PRIMJER B EXAMPLE B
N-acetil-N-[l- (2-piperidino-fenil) -3-metil-1-buten-1-il]-amin N-acetyl-N-[1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl]-amine
U otopinu 20 g (81,8 mmola) sviježe priređenog izobutil-(2-piperidino-fenil)-ketimina u 200 ml acetonitrila stavimo pri sobnoj temperaturi 4,7 ml (81,8 mmola) ledene octene kiseline, 25,7 g ( 98,2 mmola) trifenilfosfina, 34,2 ml (245 mmola) trietilamina i 7,9 ml ( 81,8 mmola) tetraklorugljika, te miješamo 18 sati pri sobnoj temperaturi. Potom uparimo u vakuumu i porazdijelimo između etilacetata i vode. Organski ekstrakt posušimo i filtriramo, te ga uparimo u vakuumu. Upareni ostatak čistimo kromatografski u koloni na silikagelu (toluol/etilacetat = 10/1), pri čemu najprije eluiramo (E)-oblik i potom (Z)-oblik. 4.7 ml (81.8 mmol) of glacial acetic acid, 25.7 g ( 98.2 mmol) of triphenylphosphine, 34.2 ml (245 mmol) of triethylamine and 7.9 ml (81.8 mmol) of carbon tetrachloride, and stirred for 18 hours at room temperature. Then evaporate in a vacuum and distribute between ethyl acetate and water. The organic extract is dried and filtered, and evaporated in a vacuum. The evaporated residue is purified by column chromatography on silica gel (toluene/ethylacetate = 10/1), whereby first the (E)-form and then the (Z)-form are eluted.
(E)-oblik: (E)-form:
Iskorištenje: 6,1 g (26 % teor.) Yield: 6.1 g (26 % of theory)
tal.: 135-137°C (etilacetat/petroleter) m.p.: 135-137°C (ethyl acetate/petroleum ether)
[image] [image]
(Z)-oblik: (Z)-form:
Iskorištenje: 3,1 g (13 % teor.) Yield: 3.1 g (13 % of theory)
tal.: 140-143°C (etilacetat) melting point: 140-143°C (ethyl acetate)
[image] [image]
PRIMJER C EXAMPLE C
N-acetil-N-[1- (2-piperidino-fenil) -3-metil-1-buten-1-il]-amin N-acetyl-N-[1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl]-amine
U otopinu 44 g (0,18 mola) sviježe priređenog izobutil-(2-piperidino-fenil)-ketimina u 440 ml toluola uz miješanje dokapavamo 17 ml (0,18 mola) acetanhidrida pri unutarnjoj temperaturi 0°C. Miješamo još 3 sata pri 0°C i 15 sati pri sobnoj temperaturi, potom uparimo u vakuumu, otopimo upareni ostatak u etilacetatu i više puta ga protresemo s vodenom otopinom natrijeva hidrogenkarbonata. Organsku fazu posušimo, filtriramo i uparimo u vakuumu. Upareni ostatak očistimo kromatografski u koloni na silikagelu (toluol/etilacetat 5/1), pri čemu najprije eluiramo (E)-oblik i potom (Z)-oblik. In a solution of 44 g (0.18 mol) of freshly prepared isobutyl-(2-piperidino-phenyl)-ketimine in 440 ml of toluene, 17 ml (0.18 mol) of acetic anhydride are added dropwise with stirring at an internal temperature of 0°C. Stir for another 3 hours at 0°C and 15 hours at room temperature, then evaporate in a vacuum, dissolve the evaporated residue in ethyl acetate and shake it several times with an aqueous solution of sodium bicarbonate. The organic phase is dried, filtered and evaporated in a vacuum. The evaporated residue is purified by column chromatography on silica gel (toluene/ethyl acetate 5/1), whereby first the (E)-form and then the (Z)-form are eluted.
(E)-oblik: (E)-form:
Iskorištenje: 3,0 g (5,8 % teor.) Yield: 3.0 g (5.8% theoretical)
(Z)-oblik: (Z)-form:
Iskorištenje: 17,8 g (34,5 % teor.) Yield: 17.8 g (34.5 % of theory)
tal.: 139-141°C (etilacetat) m.p.: 139-141°C (ethyl acetate)
[image] [image]
PRIMJER D EXAMPLE D
N-acetil-N-[ (S) -1- (2-piperidino-fenil) -3-metil-1-butil]-amin N-acetyl-N-[(S)-1-(2-piperidino-phenyl)-3-methyl-1-butyl]-amine
0,57 g (1,99 mmola) (Z)-N-acetil-N-[1-(2-piperidino-fenil)-3-metil-1-buten-1-il]amina s tal. 139 do 141°C otopimo u 10 ml rasplinjene smjese otapala (metanol/metilenklorid = 5/1) u atmosferi argona i u otopinu stavimo 16,8 mg (1 mol %) NOYORI-katalizatora Ru(O-acetil)2[(S)-BINAP] (priređen iz [Ru(COD)Cl2]n sa (S)-BINAP[=(S)-2,2'-bis(difenilfosfino)-1,1'-binaftil], trietilaminom i natrijevim acetatom) i 3,4 mg (0,5 mol %) titanova tetraizopropilata u 10 ml rasplinjene smjese otapala (metanol/metilenklorid = 5/1). Reakcijsku smjesu stavimo u autoklav, evakuiran pri 10-2 mbara. Više puta isperemo s vodikom s 4 bara i potom hidriramo pri 30°C i 100 bara do završetka vezivanja vodika (170 sati) . Potom smeđe crvenu otopinu- uparimo u vakuumu, kuhamo uz refluks upareni ostatak s 30 ml n-heksana i neotopljeno vruče odfiltriramo. Pri hlađenju filtrata dolazi do kristalizacije. 0.57 g (1.99 mmol) of (Z)-N-acetyl-N-[1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl]amine with m.p. 139 to 141°C, dissolve in 10 ml of gasified solvent mixture (methanol/methylene chloride = 5/1) in an argon atmosphere and add 16.8 mg (1 mol %) of NOYORI catalyst Ru(O-acetyl)2[(S) -BINAP] (prepared from [Ru(COD)Cl2]n with (S)-BINAP[=(S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl], triethylamine and sodium acetate) and 3.4 mg (0.5 mol %) of titanium tetraisopropylate in 10 ml of a gaseous solvent mixture (methanol/methylene chloride = 5/1). Place the reaction mixture in an autoclave, evacuated at 10-2 mbar. Wash several times with hydrogen at 4 bar and then hydrate at 30°C and 100 bar until hydrogen bonding is complete (170 hours). Then evaporate the brown-red solution in a vacuum, boil the evaporated residue with 30 ml of n-hexane under reflux and filter off the undissolved hot solution. Crystallization occurs when the filtrate is cooled.
Iskorištenje: 0,31 g (54 % teor.) Yield: 0.31 g (54 % of theory)
Tal.: 127-131°C Melting point: 127-131°C
Enantiomerna čistoća: ee = 82% (S) [HPLC-metoda: vidi primjer A]. Enantiomeric purity: ee = 82% (S) [HPLC method: see example A].
Iz neotopljenog, dobivenog pri kuhanju s 30 ml n-heksana, se da s daljim kuhanjem s n-heksanom, filtriranjem i kristalizacijom iz heksanske otopine dobiti 14 % racemičnog N-acetil-amina s tal. 154-156°C. 14% of racemic N-acetyl-amine with m.p. 154-156°C.
PRIMJER E EXAMPLE E
(S)-1-(2-piperidino-fenil)-3-metil-1-butil-amin (S)-1-(2-piperidino-phenyl)-3-methyl-1-butyl-amine
Zagrijavamo 1 g (3,47 mmola) N-acetil-N-[(S)-1-(2-piperidino-fenil)-3-metil-1-butil]-amina (tal.: 128-133°C; ee = 99,4 %) u 10 ml koncentrirane solne kiseline 5,5 sati uz refluks, ohladimo i izlijemo u smjesu koncentriranog amonijaka i leda. 2-puta ekstrahiramo s etilacetatom, organsku fazu isperemo vodom, posušimo i filtriramo, te uparimo u vakuumu. We heat 1 g (3.47 mmol) of N-acetyl-N-[(S)-1-(2-piperidino-phenyl)-3-methyl-1-butyl]-amine (m.p.: 128-133°C; ee = 99.4 %) in 10 ml of concentrated hydrochloric acid for 5.5 hours under reflux, cool and pour into a mixture of concentrated ammonia and ice. Extract twice with ethyl acetate, wash the organic phase with water, dry and filter, and evaporate in a vacuum.
Iskorištenje: 0,84 g (98,8 % teor.) uljastog amina. Yield: 0.84 g (98.8 % of theory) of oily amine.
Povratnim acetiliranjem s 0,42 ml (1,3 ekvivalenta) acetanhidrida u 8,4 ml ledene octene kiseline preko noći pri sobnoj temperaturi, uparavanjem u vakuumu, porazdjeljenjem uparenog ostatka između etilacetata i zasićene vodene otopine natrijeva karbonata kao i sa sušenjem, filtriranjem i uparavanjem organskog ekstrakta u vakuumu dobijemo 0,83 g (84,7 % teor.) N-acetil-N-[(S)-1-(2-piperidino-fenil)-3-metil-1-butil]-amina (tal.: 130-132°C; ee = 99,4 %) . Back-acetylation with 0.42 ml (1.3 equiv) of acetic anhydride in 8.4 ml of glacial acetic acid overnight at room temperature, evaporation in vacuo, partitioning the evaporated residue between ethyl acetate and saturated aqueous sodium carbonate, as well as drying, filtering and evaporation of the organic extract in a vacuum gives 0.83 g (84.7 % of theory) of N-acetyl-N-[(S)-1-(2-piperidino-phenyl)-3-methyl-1-butyl]-amine ( mp: 130-132°C; ee = 99.4%).
PRIMJER F EXAMPLE F
Etilester 2-etoksi-4-[N-(1-(2-piperidino-fenil)-3-metil-1-buten-1-il)-aminokarbonilmetilj-benzojeve kiseline 2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl)-aminocarbonylmethyl-benzoic acid ethyl ester
Pripravljen iz izobutil-(2-piperidino-fenil)-ketimina i 3-etoksi-4-etoksikarbonil-feniloctene kiseline analogno primjeru B. Kromatografsko čišćenje u koloni na silikagelu (toluol/aceton = 10/1), pri čemu najprije eluiramo (E)-oblik i potom (Z)-oblik. Prepared from isobutyl-(2-piperidino-phenyl)-ketimine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid analogously to example B. Chromatographic purification in a column on silica gel (toluene/acetone = 10/1), whereby we first elute (E )-form and then (Z)-form.
(E)-oblik: (E)-form:
Iskorištenje: 4 % teor., Utilization: 4 % theor.,
tal.: 101-103°C melting point: 101-103°C
[image] [image]
(Z)-oblik: (Z)-form:
Iskorištenje: 28,1 % teor., Utilization: 28.1 % of theory,
tal.: 124-127°C (petroleter/toluol = 5/1) m.p.: 124-127°C (petroleum ether/toluene = 5/1)
[image] [image]
PRIMJER G EXAMPLE Mr
N-[ (S')-1-fenetil]-N-[ (S)-1-(20piperidino-fenil)-3-metil-1-butil]-amin N-[(S')-1-phenethyl]-N-[(S)-1-(20piperidino-phenyl)-3-methyl-1-butyl]-amine
17 g (49 mmola) N-[(S')-1-fenetil]-izobutil-(2-piperidino-fenil)-ketimina s vrelištem 150-155°C/0,4 mbara [pripravljen iz izobutil-(2-pipiridino-fenil)-ketona i (S')-1-fenetil-amina (tvrtka Fluka, ee = 99, 6 %) u toluolu + trietilaminu s dokapavanjem otopine titanova tetraklorida u toluolu] otopimo u 170 ml bezvodnog etanola. Dodajemo 1,7 g titanova tetraizopropilata i 8 g Raneyevog nikla te hidriramo pri 50°C i 200 bara vodika. Poslije 20 sati dodajemo daljnjih 8 g Raneyevog nikla i hidriramo uz jednake uvjete još 52 sati. Katalizator odfiltriramo preko sloja celita na nuči-G3 i filtrat uparimo u vakuumu. 17 g (49 mmol) of N-[(S')-1-phenethyl]-isobutyl-(2-piperidino-phenyl)-ketimine with a boiling point of 150-155°C/0.4 mbar [prepared from isobutyl-(2- of piperidino-phenyl)-ketone and (S')-1-phenethyl-amine (Fluka company, ee = 99.6%) in toluene + triethylamine with dropwise addition of a solution of titanium tetrachloride in toluene] dissolve in 170 ml of anhydrous ethanol. We add 1.7 g of titanium tetraisopropylate and 8 g of Raney's nickel and hydrate at 50°C and 200 bar of hydrogen. After 20 hours, we add a further 8 g of Raney's nickel and hydrate under the same conditions for another 52 hours. The catalyst is filtered over a layer of celite on a G3 plate and the filtrate is evaporated in a vacuum.
Iskorištenje: 13,1 g (76,6 % teor.) Yield: 13.1 g (76.6 % of theory)
Tal.: 152°C/0,27 mbara Melting point: 152°C/0.27 mbar
[image] [α]D20= -55,3° (c = 1,1 u metanolu) [image] [α]D20= -55.3° (c = 1.1 in methanol)
Dijastereomernu čistoću odredimo pomoću HPLC na Lichrosorb RP18-HPLC koloni tvrtke E. Merck (Njemačka); dužina kolone: 250 mm uz unutarnji promjer 4 mm, veličina čestica: 7 µm; eluirno sredstvo: metanol/dioksan/0,1%-na vodena otopina natrijeva acetata, namještena s octenom kiselinom na pH = 4,05 (135/60/5); temperatura: 23°C; UV-detekcija pri 254 nm. Diastereomeric purity was determined using HPLC on a Lichrosorb RP18-HPLC column from E. Merck (Germany); column length: 250 mm with an inner diameter of 4 mm, particle size: 7 µm; eluent: methanol/dioxane/0.1% aqueous sodium acetate, adjusted with acetic acid to pH = 4.05 (135/60/5); temperature: 23°C; UV detection at 254 nm.
Ustan.: Peak 1(S,S'): Peak 2(R,S') = 98,4 %: 1,4 %, Est.: Peak 1(S,S'): Peak 2(R,S') = 98.4 %: 1.4 %,
de (diastereomeric excess) = 97,0 % (S.S'). de (diastereomeric excess) = 97.0 % (S.S').
PRIMJER H EXAMPLE H
(S)-1-(2-piperidinofenil)-3-metil-1-butilamin (S)-1-(2-piperidinophenyl)-3-methyl-1-butylamine
12,5 g (36 mmola) N-[ (S')-1-fenetil]-N-[(S)-1-(2-piperidino-fenil)-3-metil-1-butil]-amina s de = 97,0% (S.S') otopimo u 125 ml vode i 3,6 ml koncentrirane solne kiseline. Dodajemo 1,3 g paladija/ugljena (10 %) i hidriramo pri 50°C i 5 bara vodika. Poslije završenog vezivanja vodika (10 sati) odfiltriramo katalizator preko celitnog sloja. Filtrat zalužimo koncentriranim amonijakom uz dodatak leda i ekstrahiramo s etilacetatom. Organski ekstrakt posušimo i ekstrahiramo s etilacetatom. Organski ekstrakt posušimo i filtriramo, te uparimo u vakuumu. 12.5 g (36 mmol) of N-[(S')-1-phenethyl]-N-[(S)-1-(2-piperidino-phenyl)-3-methyl-1-butyl]-amine with de = 97.0% (S.S') dissolve in 125 ml of water and 3.6 ml of concentrated hydrochloric acid. We add 1.3 g of palladium/charcoal (10%) and hydrate at 50°C and 5 bar of hydrogen. After the completion of hydrogen bonding (10 hours), the catalyst is filtered through a celite layer. The filtrate is made alkaline with concentrated ammonia with the addition of ice and extracted with ethyl acetate. The organic extract is dried and extracted with ethyl acetate. The organic extract is dried and filtered, and evaporated in a vacuum.
Iskorištenje: 6,4 g (72,1 % teor.) Yield: 6.4 g (72.1 % of theory)
Tal.: 115-117°C/0,53 mbara Melting point: 115-117°C/0.53 mbar
enantiomerna čistoća: ee = 93,5 % (S) [HPLC-metoda (poslije prethodnog acetiliranja): vidi primjer A]. enantiomeric purity: ee = 93.5 % (S) [HPLC-method (after previous acetylation): see example A].
PRIMJER I EXAMPLES
N-[ (R')-1-fenetil]-N-[ (S)-1- (2-piperidino-fenil)-3-metil-1-butil]-amin N-[(R')-1-phenethyl]-N-[(S)-1-(2-piperidino-phenyl)-3-methyl-1-butyl]-amine
U kupelji pri 60°C otopini 27,4 mmola (4 ekvivalenta) izobutilmagnezijeva bromida u 22 ml bezvodnog tetrahidrofurana uz miješanje dokapavamo otopinu 2 g (6,84 mmola) N-[(R')-1-fenetil]- (2-piperidino-benzaldimina) [priređenog iz ekvimolarnih količina 2-piperidino-benzaldehida i (R')-1-fenetilamina stajanjem preko noći pri sobnoj temperaturi i zatim sušenjem s natrijevim sulfatom u eterskoj otopini] u 20 ml bezvodnog tetrahidrofurana. Poslije 18 sati povisimo temperaturu kupelji na 80°C, te dodajemo daljnja dva ekvivalenta izobutilmagnezijeva bromida u 11 ml tetrahidrofurana. Poslije svaki puta 12 satnog miješanja pri 80°C dodajemo još jednom po 2 ekvivalenta otopine izobutilmagnezijeva bromida. Nakon oko 90 sati pri 80°C ohladimo, dodajemo suvišak koncentrirane solne kiseline i u vakuumu vodenog mlaza do suhoga uparimo. Upareni ostatak otopimo u vodi i zalužimo koncentriranim amonijakom. Ekstrahiramo s eterom, organski ekstrakt posušimo iznad natrijeva sulfata, filtriramo i uparimo u vakuumu. Upareni ostatak čistimo kromatografijom u koloni na silikagelu (toluen/aceton = 95/5). In a bath at 60°C, a solution of 27.4 mmol (4 equivalents) of isobutylmagnesium bromide in 22 ml of anhydrous tetrahydrofuran is added dropwise with stirring to a solution of 2 g (6.84 mmol) of N-[(R')-1-phenethyl]-(2- piperidino-benzaldimine) [prepared from equimolar amounts of 2-piperidino-benzaldehyde and (R')-1-phenethylamine by standing overnight at room temperature and then drying with sodium sulfate in an ethereal solution] in 20 ml of anhydrous tetrahydrofuran. After 18 hours, we raise the temperature of the bath to 80°C, and add another two equivalents of isobutylmagnesium bromide in 11 ml of tetrahydrofuran. After each 12-hour mixing at 80°C, 2 equivalents of isobutylmagnesium bromide solution are added once more. After about 90 hours at 80°C, cool, add an excess of concentrated hydrochloric acid and evaporate to dryness in a water jet vacuum. The evaporated residue is dissolved in water and made alkaline with concentrated ammonia. Extract with ether, dry the organic extract over sodium sulfate, filter and evaporate in a vacuum. The evaporated residue is purified by column chromatography on silica gel (toluene/acetone = 95/5).
Iskorištenje: 0,20 g (8,3 % teor.), Yield: 0.20 g (8.3 % theory),
Tal.: <20°C Melting point: <20°C
Dijastereomernu čistoću odredimo kao u primjeru G pomoću HPLC. Diastereomeric purity is determined as in example G using HPLC.
Ustan.: Peak 1(R,R'): Peak 2(S,R') = 4,4 %: 95,6 %, Est.: Peak 1(R,R'): Peak 2(S,R') = 4.4 %: 95.6 %,
de (diastereomeric excess) = 91,2 % (S,R'). de (diastereomeric excess) = 91.2 % (S, R').
Pri analognom nastavku s 2,0 g Schiffove baze i zajedno s 6 ekvivalenta izobutilmagnezijeva bromida u toluolu/tetrahidrofuranu (4/1) kao i uz dodatak 5 % titanova(IV)-tetraizopropilata i 60 sati zagrijavanja pri 100°C u staklenoj tikvici postignemo iskorištenje od 5 % s de = 97,6 % (S,R'). In the analogous continuation with 2.0 g of Schiff's base and together with 6 equivalents of isobutylmagnesium bromide in toluene/tetrahydrofuran (4/1) as well as with the addition of 5% titanium(IV)-tetraisopropylate and 60 hours of heating at 100°C in a glass flask, we achieve utilization of 5 % with de = 97.6 % (S,R').
PRIMJER K EXAMPLE K
(S)-1-(2-piperidino-fenil)-3-metil-1-butilamin (S)-1-(2-piperidino-phenyl)-3-methyl-1-butylamine
Hidriramo otopinu 0,15 g (0,428 mmola) N-[(R')-1-fenetil]-N-[(S)-1-(2-piperidino-fenil)-3-metil-l-butil]-amina (de = 91,2 %) , 0,47 ml (0,47 mmola) 1N solne kiseline i 1,5 ml vode u prisutnosti 20 mg paladija/ugljena (10 %-ni) 5 sati pri 50°C i 3,4 bara vodika. Filtriramo preko silikagela, zalužimo koncentriranim amonijakom i ekstrahiramo s etilacetatom. Ekstrakt posušimo, filtriramo i uparimo u vakuumu. We hydrate a solution of 0.15 g (0.428 mmol) of N-[(R')-1-phenethyl]-N-[(S)-1-(2-piperidino-phenyl)-3-methyl-1-butyl]-amine (de = 91.2 %), 0.47 ml (0.47 mmol) of 1N hydrochloric acid and 1.5 ml of water in the presence of 20 mg of palladium/charcoal (10 %) for 5 hours at 50°C and 3, 4 bars of hydrogen. Filter through silica gel, make alkaline with concentrated ammonia and extract with ethyl acetate. The extract is dried, filtered and evaporated in a vacuum.
Iskorištenje: 0,066 g (62,8 % teor.), Yield: 0.066 g (62.8 % of theory),
Tal.: <20°C Melting point: <20°C
Enantiomerna čistoća: ee = 87,6 % (S) [HPLC-metoda ( poslije prethodnog acetiliranja): vidi primjer A]. Enantiomeric purity: ee = 87.6 % (S) [HPLC-method (after previous acetylation): see example A].
PRIMJER 1 EXAMPLE 1
Etilester (S)-2-etoksi-4-[N-(1-(2-piperidino-fenil)-3-metil-1-butil) -aminokarbonilmetil]-benzojeve kiseline (S)-2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester
U otopinu 0,47 g (1,91 mmola) (S)-3-metil-1-(2-piperidino-fenil)-1-butilamina (ee=98,5 %) u 5 ml bezvodnog acetonitrila dodajemo redom 0,48 g (1,91 mmola) 3-etoksi-4-etoksikarbonil-feniloctene kiseline, 0,60 g (2,29 mmola) trifenilfosfina, 0,80 ml (5,73 mmola) trietilamina i 0,18 ml (1,91 mmola) tetraklorugljika, te miješamo 20 sati pri sobnoj temperaturi. Potom uparimo u vakuumu te porazdijelimo između etilacetata i vode. Organski ekstrakt posušimo i filtriramo, te uparimo u vakuumu. Upareni ostatak čistimo kromatografski u koloni na silikagelu (toluol/etilacetat = 10/1). To a solution of 0.47 g (1.91 mmol) of (S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine (ee=98.5 %) in 5 ml of anhydrous acetonitrile, add 0, 48 g (1.91 mmol) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid, 0.60 g (2.29 mmol) of triphenylphosphine, 0.80 ml (5.73 mmol) of triethylamine and 0.18 ml (1, 91 mmol) of carbon tetrachloride, and stir for 20 hours at room temperature. Then evaporate in a vacuum and distribute between ethyl acetate and water. The organic extract is dried and filtered, and evaporated in a vacuum. The evaporated residue is purified by column chromatography on silica gel (toluene/ethyl acetate = 10/1).
Iskorištenje: 0,71g (77,3 % teor.), Yield: 0.71g (77.3% theory),
Tal. = 110-112°C Tal. = 110-112°C
[image] [image]
Enantiomernu čistoću odredimo pomoću HPLC na HPLC-koloni s kiralnim fazama tvrtke Baker, pri kojoj je (S)-N 3,5-dinitrobenzoil-leucin kovalentno vezan na aminopropil-silikagel. Veličina zrna: 5 µm, kuglasta, širina pora: 60 nm; Enantiomeric purity is determined by HPLC on an HPLC column with chiral phases from the company Baker, where (S)-N 3,5-dinitrobenzoyl-leucine is covalently bound to aminopropyl-silica gel. Grain size: 5 µm, spherical, pore width: 60 nm;
dužina kolone: 250 mm sa unutarnjim promjerom 4,6 mm; eluirno sredstvo: n-heksan/tetrahidrofuran/ metilen klorid/etanol (90/10/1/1); brzina eluiranja: 2 ml/min; temperatura: 20°C; column length: 250 mm with an internal diameter of 4.6 mm; eluent: n-hexane/tetrahydrofuran/methylene chloride/ethanol (90/10/1/1); elution rate: 2 ml/min; temperature: 20°C;
UV-detekcija pri 242 nm. UV detection at 242 nm.
Ustan.: Peak 1(R): Peak 2(S) = 0,75 %: 99,25 %, Est.: Peak 1(R): Peak 2(S) = 0.75 %: 99.25 %,
ee = 98,5 % (S) . ee = 98.5% (S) .
PRIMJER 2 EXAMPLE 2
Etilester (S)-2-etoksi-4-[N-(1-(2-piperidino-fenil)-3-metil-1-butil) -aminokarbonilmetil]-benzojeve kiseline (S)-2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester
U otopinu 2,71 g (11 mmola) bezvodnog (S)-3-metil-1-(2-piperidino-fenil)-1-butilamina (ee=98,5 %) u 30 ml apsolutnog toluola dodajemo pri sobnoj temperaturi 2,77 g (11 mmola) 3-etoksi-4-etoksikarbonil-feniloctene kiseline i miješamo sve dok ne nastaje otopina. Potom dodajemo 2,38 g (11,55 mmola) N.N'-dicikloheksilkarbodiimida i miješamo pri sobnoj temperaturi. Poslije 24 sata dodajemo još 0,54 g (2,14 mmola) 3-etoksi-4-etoksikarbonil-feniloctene kiseline i 0,48 g (2,33 mmola) N,N'-dicikloheksil-karbodiimida, te miješamo preko noći. Zatim ohladimo na unutarnju temperaturu +5°C i odfiltriramo istaloženo preko nuče, koje isperemo jednom s 5 ml toluola. Spojene toluolne filtrate uparimo u vakuumu na volumen od oko 10 ml. Tako dobivenu otopinu zagrijemo na parnoj kupelji i dodajemo u obrocima petroleter (zajedno 55 ml) do trajne zamućenosti. Ohladimo u ledu, pri čemu dolazi do kristalizacije. Odfiltriramo preko nuče i sušimo pri 75°C/5,3 mbara. Dobiveni produkt (4,57 g; tal. 111-112°C; ee=98,9 %) suspendiramo u 50 ml petroletera. Zagrijemo na parnoj kupelji i dodajemo u obrocima toliko toluola (zajedno 8 ml) , dok ne nastaje otopina. Potom ohladimo u ledu i kristale odfiltriramo preko nuče, te ih sušimo pri 75°C/5,3 mbara. In a solution of 2.71 g (11 mmol) of anhydrous (S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine (ee=98.5%) in 30 ml of absolute toluene, at room temperature 2 .77 g (11 mmol) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid and mix until a solution is formed. Then add 2.38 g (11.55 mmol) of N,N'-dicyclohexylcarbodiimide and mix at room temperature. After 24 hours, add another 0.54 g (2.14 mmol) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid and 0.48 g (2.33 mmol) of N,N'-dicyclohexyl-carbodiimide, and stir overnight. Then cool down to an internal temperature of +5°C and filter off the precipitate through a sieve, which is washed once with 5 ml of toluene. The combined toluene filtrates are evaporated in a vacuum to a volume of about 10 ml. We heat the solution obtained in this way on a steam bath and add petroleum ether in portions (55 ml in total) until permanent cloudiness. Cool in ice, during which crystallization occurs. We filter it through a sieve and dry it at 75°C/5.3 mbar. The obtained product (4.57 g; m.p. 111-112°C; ee=98.9%) is suspended in 50 ml of petroleum ether. Heat on a steam bath and add as much toluene in portions (8 ml in total) until a solution is formed. Then we cool it in ice and filter the crystals through a sieve, and dry them at 75°C/5.3 mbar.
Iskorištenje: 3,93 g (74,3 % teor.), Yield: 3.93 g (74.3 % of theory),
tal.: 117-118°C melting point: 117-118°C
[image] [α]D20= +9/4º (c = 1,01 u metanolu) [image] [α]D20= +9/4º (c = 1.01 in methanol)
Enantioinerna čistoća: ee = 99,9 % [HPLC-metoda: vidi primjer 1]. Enantioiner purity: ee = 99.9 % [HPLC method: see example 1].
PRIMJER 3 EXAMPLE 3
(S) -2-etoksi-4-[N- (1- (2-piperidino-fenil) -3-metil-1-butil) -aminokarbonilmetil]-benzojeva kiselina (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid
Otopinu 3,79 g (7,88 mmola) etilestera (S)-2-etoksi-4-[N- (1-(2-piperidino-fenil)-3-metil-1-butil)-aminokarbonilmetil]-benzojeve kiseline (ee=99,9 %) u 37 ml etanola miješamo u kupelji pri 60°C i dodajemo 10 ml (10 mmola) 1N natrijeve lužine. Poslije 4 sata miješanja pri 60°C u toplu dodajemo 10 ml (10 mmola) 1N solne kiseline i pustimo da se ohladi na sobnu temperaturu. Poslije otcjepljenja i stajanja preko noći hladimo uz miješanje u ledu još jedan sat. Kristale odfiltriramo preko nuče i isperemo 2-puta s po 5 ml vode. Potom sušimo pri 75°C i na kraju u vakuumskom sušioniku iznad fosforova pentoksida na 100°C/5,3 mbara. A solution of 3.79 g (7.88 mmol) of (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester (ee=99.9%) in 37 ml of ethanol, mix in a bath at 60°C and add 10 ml (10 mmol) of 1N sodium hydroxide solution. After 4 hours of stirring at 60°C, add 10 ml (10 mmol) of 1N hydrochloric acid to the warm mixture and let it cool to room temperature. After separating and standing overnight, cool with stirring in ice for another hour. The crystals are filtered through a sieve and washed twice with 5 ml of water each. Then we dry at 75°C and finally in a vacuum dryer over phosphorus pentoxide at 100°C/5.3 mbar.
Iskorištenje: 3,13 g (87,7 % teor.), Yield: 3.13 g (87.7 % of theory),
tal.: 130-131°C (oblik s visokim talištem) m.p.: 130-131°C (high melting point form)
[image] [α]D20= +7,45° (c = 1,06 u metanolu) [image] [α]D20= +7.45° (c = 1.06 in methanol)
Enantiomernu čistoću odredimo pomoću HPLC na HPLC-koloni s kiralnim fazama tvrtke ChromTech (Švedska) s AGP (α-1-kiselinski glikoprotein)-fazom; unutarnji promjer: 4,0 mm; dužina: 100 mm; promjer čestica: 5 µm. Temperatura: 20°C; eluirno sredstvo: vodena otopina KH2PO4 (=A) + 20 % acetonitrila (=B), gradijentno narastanje u 4 minuta na 40 % (B) ; brzina eluiranja: 1 ml/min; UV-detekcija pri 240 nm. Retencijko vrijeme (S)-enantiomer: 2,7 mm; retencijsko vrijeme (R)-enantiomer: 4,1 mm. Enantiomeric purity was determined using HPLC on an HPLC column with chiral phases from ChromTech (Sweden) with an AGP (α-1-acid glycoprotein) phase; inner diameter: 4.0 mm; length: 100 mm; particle diameter: 5 µm. Temperature: 20°C; eluent: aqueous solution of KH2PO4 (=A) + 20% acetonitrile (=B), gradient increase in 4 minutes to 40% (B); elution rate: 1 ml/min; UV detection at 240 nm. Retention time (S)-enantiomer: 2.7 mm; retention time (R)-enantiomer: 4.1 mm.
Ustan.: (S):(R) = 99,85 %: 0,15 %, Est.: (S):(R) = 99.85 %: 0.15 %,
ee = 99,7 % (S) . ee = 99.7% (S) .
Pri prekristalizaciji uzorka iz etanola/vode (2/1) talište se ne mijenja.. During recrystallization of the sample from ethanol/water (2/1), the melting point does not change.
Pri zagrijavanju uzorka u petroleteru/toluolu (5/3), filtriranjem neotopljivog dijela (tal.: 130-131°C) i brzim hlađenjem dobijemo oblik naslovnog spoja s niskim talištem 99-101°C. When heating the sample in petroleum ether/toluene (5/3), filtering the insoluble part (melting point: 130-131°C) and rapid cooling, we obtain the form of the title compound with a low melting point of 99-101°C.
[image] [image]
Oblici s niskim talištem i oblici s visokim talištem se razlikuju u svojim infracrvenim KBr-spektrima, dok se u svojim infracrvenim otopinskim spektrima ne razlikuju. The low-melting-point forms and the high-melting-point forms differ in their infrared KBr-spectra, while they do not differ in their infrared solution spectra.
Ako zagrijemo uzorak oblika s niskim talištem iznad njegovog tališta, primjetimo drugo talište pri 127-130°C. If we heat a sample of a form with a low melting point above its melting point, we notice a second melting point at 127-130°C.
Ako prekristaliziramo uzorak oblika s niskim talištem i to s etanol/vodom (2/1), dobijemo oblik s visokim talištem. If we recrystallize a sample of the form with a low melting point with ethanol/water (2/1), we obtain a form with a high melting point.
Oblik s visokim talištem i oblik s niskim talištem ispitamo pomoću "Differential Scanning Calorimetry (DSC)" (aparat Mettler, TA-300-sistem; mjerna stanica: DSC 20; tvrtka Mettler, CH-8306 Greifensee, Švicarska) sa slijedećim rezultatom: The high-melting-point form and the low-melting-point form are examined using "Differential Scanning Calorimetry (DSC)" (apparatus Mettler, TA-300-system; measuring station: DSC 20; company Mettler, CH-8306 Greifensee, Switzerland) with the following result:
[image] [image]
PRIMJER 4 EXAMPLE 4
Etil ester (S)-2-etoksi-4-[N-(1- (2-piperidino-fenil)-3-metil-1-butil)-aminokarbonilmetil]-benzojeve kiseline (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester
0,79 g (1,65 mmola) etilestera (Z)-2-etoksi-4-[N-(1-(2-piperidino-fenil)-3-metil-1-buten-1-il)-aminokarbonilmetil]-benzojeve kiseline s talištem 124-127°C otopimo u 10 ml rasplinjene smjese otapala (metanol/metilenklorid =5/1) u atmosferi argona i stavimo u otopinu 17 mg NOYORI-katalizatora Ru (O-acetil)2[(S)-BINAP] (priređen iz [Ru(COD)Cl2]n s (S)-BINAP [=(S)-2,2'-bis-(difenilfosfino)-1,1'-binaftil], trietilaminom i natrijevim acetatom) i 3 mg titanova tetraizopopilata u 10 ml rasplinjene smjese otapala (metanol/metilenklorid = 5/1). Reakcijsku smjesu stavimo u autoklav, evakuiran pri 10-2 mbara. 5-puta isperemo vodikom s 5 bara i potom hidriramo pri 30°C i 100 bara do kraja vezivanja vodika (154 sata). Smeđecrvenu otopinu uparimo u vakuumu, upareni ostatak otopimo u 80 ml etera, pomoću aktivnog ugljena filtriramo neotopljne smeđe pahuljice i tako dobiveni bistri svjetložuti filtrat uparimo u vakuumu. Upareni ostatak (0,60 g) kuhamo sa 60 ml n-heksana uz refluks i neotopljeno vruće filtriramo. Filtrat pustimo stajati preko noći pri sobnoj temperaturi. Pritom izlučene kristale filtriramo. 0.79 g (1.65 mmol) ethyl ester (Z)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl)-aminocarbonylmethyl] -benzoic acid with a melting point of 124-127°C is dissolved in 10 ml of a gaseous solvent mixture (methanol/methylene chloride = 5/1) in an argon atmosphere and 17 mg of NOYORI-catalyst Ru (O-acetyl)2[(S)- BINAP] (prepared from [Ru(COD)Cl2]n with (S)-BINAP [=(S)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl], triethylamine and sodium acetate) and 3 mg of titanium tetraisopopylate in 10 ml of gasified solvent mixture (methanol/methylene chloride = 5/1). Place the reaction mixture in an autoclave, evacuated at 10-2 mbar. Wash 5 times with hydrogen at 5 bar and then hydrate at 30°C and 100 bar until the end of hydrogen binding (154 hours). The brown-red solution is evaporated in a vacuum, the evaporated residue is dissolved in 80 ml of ether, the insoluble brown flakes are filtered using activated carbon and the clear light yellow filtrate thus obtained is evaporated in a vacuum. Boil the evaporated residue (0.60 g) with 60 ml of n-hexane under reflux and filter the undissolved hot. Let the filtrate stand overnight at room temperature. In doing so, we filter the secreted crystals.
Iskorištenje: 0,45 g (56,7 % teor.), Yield: 0.45 g (56.7 % of theory),
tal.: 131-133°C (poslije sintriranje iznad 120°C) m.p.: 131-133°C (after sintering above 120°C)
Enantiomerna čistoća: ee = 39% (S) [HPLC-metoda: vidi primjer 1]. Enantiomeric purity: ee = 39% (S) [HPLC method: see example 1].
PRIMJER 5 EXAMPLE 5
Etilester (S) -2-etoksi-4-[N- (1- (2-piperidino-fenil) -3-metil-1-butil) -aminokarbonilmetil]-benzojeve kiseline (S)-2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester
U otopinu 0,68 g (1,15 mmola) etilestera (S)-2-hidroksi-4-[N-(1-(2-piperidino-fenil)-3-metil-1-butil)-aminokarbonilmetil]-benzojeve kiseline [tal. : 125-126°C; [α]D20= +12,87° (c = 1,01 u metanolu)] u 5 ml bezvodnog dimetilforamida stavimo 0,05 g (1,15 mmola) natrijeva hidrida/55 %-tni u ulju i miješamo 0,5 sati pri sobnoj temperaturi. Potom dokapavamo otpinu 0,12 ml (1,15 mmola) etiljodida u 2,5 ml bezvodnog dimetilforamida i miješamo 5 sati pri sobnoj temperaturi. Uparimo u vakuumu, porazdijelimo između razrijeđene natrijeve lužine i kloroforma, organski ekstrakt posušimo, filtriramo i uparimo u vakuumu. Upareni ostatak čistimo kolonskom komatografijom na silikagelu (toluol/etilacetat = 10/1). In a solution of 0.68 g (1.15 mmol) of ethyl ester (S)-2-hydroxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid acids [m.p. : 125-126°C; [α]D20= +12.87° (c = 1.01 in methanol)] add 0.05 g (1.15 mmol) of sodium hydride/55% in oil to 5 ml of anhydrous dimethylformamide and mix 0.5 hours at room temperature. Then a solution of 0.12 ml (1.15 mmol) of ethyl iodide in 2.5 ml of anhydrous dimethylformamide is added dropwise and stirred for 5 hours at room temperature. Evaporate in a vacuum, distribute between dilute sodium hydroxide solution and chloroform, dry the organic extract, filter and evaporate in a vacuum. The evaporated residue is purified by column chromatography on silica gel (toluene/ethyl acetate = 10/1).
Iskorištenje: 0,48 g (67 % teor.), Yield: 0.48 g (67 % of theory),
tal.: 110-112°C melting point: 110-112°C
[image] Enantiomerna čistoća: ee = 98,5 % (S) [HPLC-metoda: vidi primjer 1]. [image] Enantiomeric purity: ee = 98.5 % (S) [HPLC method: see example 1].
PRIMJER 6 EXAMPLE 6
Etilester (S)-2-etoksi-4-[N-(1-(2-piperidino-fenil)-3-metil-1-butil)-aminokarbonilmetil]-benzojeve kiseline (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester
Priređen iz (S)-2-hidroksi-4-[N-(1-(2-piperidino-fenil)-3-metil-1-butil) -aminokarbonilmetil]-benzojeve kiseline, analogno primjeru 5, s 2 ekvivalenata natrijeva hidrida i 2 ekvivalenata etiljodida. Prepared from (S)-2-hydroxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid, analogously to example 5, with 2 equivalents of sodium hydride and 2 equivalents of ethyl iodide.
Iskorištenje: 42 % teor., Utilization: 42% theoretical,
tal.: 110-112°C melting point: 110-112°C
[image] Enantiomerna čistoća: ee = 98,3 % (S) [HPLC-metoda: vidi primjer 1]. [image] Enantiomeric purity: ee = 98.3 % (S) [HPLC method: see example 1].
PRIMJER 7 EXAMPLE 7
Etilester(S) (+)-2-etoksi-4-[N-(1-(2-piperidino-fenil)-3-metil-1-butil)-aminokarbonilinetilj-benzojeve kiseline i etilester (R) (-)-2-etoksi-4-[N-(1-(2-piperidino-fenil)-3-metil-1-butil)-aminokarbonilmetil]-benzojeve kiseline Ethyl ester (S) (+)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylethyl-benzoic acid and ethyl ester (R) (-)- 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid
920 mg etilestera (±) -2-etoksi-4-[N- (1- (2-piperidino-fenil) -3-metil-1-butil)-aminokarbonilmetil]-benzojeve kiseline odvojimo u pojedinačnim dozama od po 10 mg na preparativnoj HPLC koloni s kiralnim fazama tvrtke Baker, pri kojoj je (S)-N-3,5-dinitrobenzoil-leucin kovalentno vezan na aminopropil-silikagel. (Veličina zrna 40 um; dužina kolone: 250 mm unutarnjeg pomjera 20 mm; eluirno sredstvo: n-heksan/tetrahidrofuran/etanol/metilenklorid (180/20/3/2) ; brzina eluiranja: 21,25 ml/min; temperatura: 27°C; UV-detekcija pri 285 nm) , pri čemu najprije eluiramo (R) (-)-enantiomer (Peak 1) i potom (S)(+)-enantiomer (Peak 2). 920 mg of (±)-2-ethoxy-4-[N- (1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester is separated in individual doses of 10 mg per preparative HPLC column with chiral phases from Baker, where (S)-N-3,5-dinitrobenzoyl-leucine is covalently bound to aminopropyl silica gel. (Grain size 40 um; column length: 250 mm internal displacement 20 mm; eluent: n-hexane/tetrahydrofuran/ethanol/methylene chloride (180/20/3/2) ; elution rate: 21.25 ml/min; temperature: 27°C; UV-detection at 285 nm), whereby we first elute the (R) (-)-enantiomer (Peak 1) and then the (S)(+)-enantiomer (Peak 2).
Iz odgovarajuće izdvojenih i sakupljenih frakcija poslije uparavanja u vakuumu dobijemo: From the appropriately separated and collected fractions, after evaporation in a vacuum, we get:
Frakcija "Peak 1" (R): 423 mg (sirovi), Fraction "Peak 1" (R): 423 mg (raw),
Frakcija "Peak 2" (S): 325 mg (sirovi). Fraction "Peak 2" (S): 325 mg (raw).
Za odvajanje nečistoća (među drugima stabilizatora 2,6-di-terc-butil-4-metilfenola, kojeg sadrži tetrahidrofuran) obje frakcije svaki puta čistimo kromatografijom u koloni na silikagelu (toluol/aceton = 10/1). To separate impurities (among others, the stabilizer 2,6-di-tert-butyl-4-methylphenol, which contains tetrahydrofuran), both fractions are purified each time by column chromatography on silica gel (toluene/acetone = 10/1).
(R)(-)-enantiomer: (R)(-)-enantiomer:
Iskorištenje: 234,5 mg (51 % teor.), Yield: 234.5 mg (51 % of theory),
tal.: 122-124°C (petroleter + aceton) m.p.: 122-124°C (petroleum ether + acetone)
[image] [α]D20= -8,3° (c = 1 u metanolu) (S)-enantiomer: [image] [α]D20= -8.3° (c = 1 in methanol) (S)-enantiomer:
Iskorištenje: 131,2 mg (28,5 % teor.), Yield: 131.2 mg (28.5% theory),
tal.: 122-124°C (petroleter/aceton = 8/1) melting point: 122-124°C (petroleum ether/acetone = 8/1)
[image] [α]D20= +8,3° (c = 1 u metanolu) [image] [α]D20= +8.3° (c = 1 in methanol)
Za odvajanje enantiomera također je prikladna Chiralcel OD-kolona tvrtke Daicel. Na koloni dužine 250 mm i unutarnjeg promjera 4,6 mm (eluirno sredstvo: apsolutni etanol/n-heksan + 0,2 % dietilamina) = 5/95; temperatura: 40°C; UV detekcija pri 245 nm) eluiramo (R)-enantiomer poslije 6,8 minuta i (S) enantiomer poslije 8,5 minuta. A Chiralcel OD column from Daicel is also suitable for enantiomer separation. On a column with a length of 250 mm and an internal diameter of 4.6 mm (eluent: absolute ethanol/n-hexane + 0.2% diethylamine) = 5/95; temperature: 40°C; UV detection at 245 nm) we elute the (R)-enantiomer after 6.8 minutes and the (S)-enantiomer after 8.5 minutes.
PRIMJER 8 EXAMPLE 8
(R) (-)-2-etoksi-4-[N-(1-(2-piperidino-fenil)-3-metil-1-butil)-aminokarbonilmetil]-benzojeva kiselina x 0,4 H2O (R) (-)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid x 0.4 H2O
Priređena iz 150 mg (0,312 mmola) etilestera (R)(-)-2-etoksi-4-[N-(1-(2-piperidino-fenil)-3-metil-1-butil)-aminokarbonil-metil]-benzojeve kiseline [tal.: 122-124°C; Prepared from 150 mg (0.312 mmol) ethyl ester (R)(-)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonyl-methyl]- benzoic acid [melt.: 122-124°C;
[α]D20= -8,3° (c = 1 u metanolu)] saponifikacijom s 1N natrijevom lužinom u etanolu analogno primjeru 3. [α]D20= -8.3° (c = 1 in methanol)] by saponification with 1N sodium hydroxide solution in ethanol analogously to example 3.
Iskorištenje: 95,8 mg (66,7 % teor.), Yield: 95.8 mg (66.7 % of theory),
tal.: 103 - 105°C (toluol/petroleter) m.p.: 103 - 105°C (toluene/petroleum ether)
[image] Molarni peak M+: izrač.: 452 [image] Molar peak M+: calc.: 452
ustan: 452 mouth: 452
[α]D20 =6,50 (c = 1 u metanolu) [α]D20 =6.50 (c = 1 in methanol)
Enantiomerna čistoća: ee = 99,7 % (R) [HPLC-metoda: vidi primjer 3]. Enantiomeric purity: ee = 99.7 % (R) [HPLC method: see example 3].
PRIMJER 9 EXAMPLE 9
(S)(+)-2-etoksi-4-[N-(1-(2-piperidino-fenil)-3-metil-1-butil)-aminokarbonilmetil]-benzojeva kiselina x 0,4 H2O (S)(+)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid x 0.4 H2O
Priređena iz 89 mg (0,198 mmola) etilestera (S)(+)-2-etoksi-4-[N-(1-(2-piperidino-fenil)-3-metil-1-butil)-aminokarbonilmetil]-benzojeve kiseline [tal. : 122-124°C; [α]D20 = +8,3° (c = 1 u metanolu)] saponifikacijom s 1N natrijevom lužinom u etanolu analogno primjeru 3. Prepared from 89 mg (0.198 mmol) ethyl ester (S)(+)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid [tal. : 122-124°C; [α]D20 = +8.3° (c = 1 in methanol)] by saponification with 1N sodium hydroxide solution in ethanol analogously to example 3.
Iskorištenje: 44,5 mg (48,8 % teor.), Yield: 44.5 mg (48.8% theoretical),
tal.: 102-103°C (toluol/petroleter) m.p.: 102-103°C (toluene/petroleum ether)
[image] [α]D20= +6,7° (c = 1 u metanolu) [image] [α]D20= +6.7° (c = 1 in methanol)
Enantiomerna čistoća: ee = 99,6 % (S) [HPLC-metoda: vidi primjer 3]. Enantiomeric purity: ee = 99.6 % (S) [HPLC method: see example 3].
PRIMJER 10 EXAMPLE 10
(S)-2-etoksi-4-[N-(1-(2-piperidino-fenil)-3-metil-1-butil)-aminokarbonilmetil]-benzojeva kiselina (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid
Hidriramo 0,26 g (0,47 mmola) benzilestera (S)-2-etoksi-4-[N-(1-(2-piperidino-fenil)-3-metil-1-butil)-aminokarbonilmetil]-benzojeve kiseline (tal.: 91-92°C; [α]D20= +9,5°; c = 1,05 u metanolu) u 10 ml etanola na 0,12 g paladija/ugljena (10 %-tni) pri 50°C i 5 bara vodika. Poslije 5 sati odfiltriramo katalizator preko Kieselgura i uparimo u vakuumu. Upareni ostatak kristaliziramo iz etanola/vode (2/1). We hydrate 0.26 g (0.47 mmol) of benzyl ester (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid (mp: 91-92°C; [α]D20= +9.5°; c = 1.05 in methanol) in 10 ml ethanol on 0.12 g palladium/charcoal (10%-tn) at 50° C and 5 bars of hydrogen. After 5 hours, the catalyst is filtered through Kieselgur and evaporated in a vacuum. The evaporated residue is crystallized from ethanol/water (2/1).
Iskorištenje: 0,15 g (70 % teor.), Yield: 0.15 g (70% theoretical),
tal.: 130-131°C melting point: 130-131°C
[image] Enantiomerna čistoća: ee = 99,6 % (S) [HPLC-metoda: vidi primjer 3]. [image] Enantiomeric purity: ee = 99.6 % (S) [HPLC method: see example 3].
PRIMJER 11 EXAMPLE 11
(S)-2-etoksi-4-[N-(1-(2-piperidino-fenil)-3-metil-1-butil)-aminokarbonilmetilj-benzojeva kiselina (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl-benzoic acid
102 mg (0,20 mmola) terc-butilestera (S)-2-etoksi-4-[N-(1-(2-piperidino-fenil)-3-metil-1-butil)-aminokarbonilmetil]-benzojeve kiseline (tal.: 122-123°C; [α]D20= +8,7°; c = 1 u metanolu) u 5 ml benzola zagrijavamo pola dana uz refluks zajedno s nekoliko kristala hidrata p-toluolsulfonske kiseline. Potom poslije tankoslojne komatografije prema vrijednosti RF i masenom spektru nastaje željeni produkt. Tal.: 129-131°C 102 mg (0.20 mmol) tert-butyl ester (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid ( m.p.: 122-123°C; [α]D20= +8.7°; c = 1 in methanol) in 5 ml of benzene is heated for half a day under reflux together with several crystals of p-toluenesulfonic acid hydrate. Then, after thin-layer chromatography according to the RF value and the mass spectrum, the desired product is created. Melting point: 129-131°C
Molarni peak M+: izrač. : 452 Molar peak M+: calcd. : 452
ustan: 452 mouth: 452
PRIMJER 12 EXAMPLE 12
(S)-2-etoksi-4-[N-(1-(2-piperidino-fenil)-3-metil-1-butil)-aminokarbonilmetil]-benzojeva kiselina (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid
200 mg (0,395 mmola) terc-butilestera (S)-2-etoksi-4-[N-(1-(2-piperidino-fenil)-3-metil-1-butil)-aminokarbonilmetil]-benzojeve kiseline (tal. 122-123°C; [α]D20= +8,7°; (c = 1, u metanolu)] u 2 ml etilenklorida miješamo preko noći pri sobnoj temperaturi zajedno s 0,45 g (3,95 mmola) trifluoroctene kiseline. Uparimo u vakuumu i upareni ostatak porazdijelimo između vodene otopine natrijeva hidrogenkarbonata i etilacetata. Organski ekstrakt posušimo, filtriramo i uparimo u vakuumu. Upareni ostatak kristaliziramo iz etanola/vode (2/1). 200 mg (0.395 mmol) of tert-butyl ester (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid (m.p. 122-123°C; [α]D20= +8.7°; (c = 1, in methanol)] in 2 ml of ethylene chloride is stirred overnight at room temperature together with 0.45 g (3.95 mmol) of trifluoroacetic acid Evaporate in a vacuum and distribute the evaporated residue between an aqueous solution of sodium hydrogencarbonate and ethyl acetate. Dry the organic extract, filter and evaporate in a vacuum. Crystallize the evaporated residue from ethanol/water (2/1).
Iskorištenje: 115 mg (64,7 % teor.), Yield: 115 mg (64.7% theoretical),
tal.: 126-128°C melting point: 126-128°C
[image] [α]D20 = +6,97° (c = 0,975 u metanolu) [image] [α]D20 = +6.97° (c = 0.975 in methanol)
Enantiomerna čistoća: ee = 99,6% [HPLC-metoda: vidi primjer 3]. Enantiomeric purity: ee = 99.6% [HPLC method: see example 3].
PRIMJER 13 EXAMPLE 13
Tableta s 0,25 mg AG-EE 623 ZW Tablet with 0.25 mg AG-EE 623 ZW
Jedna tableta sadrži: One tablet contains:
0,250 mg učinkovite tvari 0.250 mg of active substance
0,125 mg N-metilglukamina 0.125 mg of N-methylglucamine
0,038 mg polivinilpirolidona 0.038 mg polyvinylpyrrolidone
0,075 mg polioksietilenpolioksipropiienskoga polimera 0.075 mg of polyoxyethylene polyoxypropylene polymer
0,150 mg mikrokristalinične celuloze 0.150 mg of microcrystalline cellulose
Priprava: Preparation:
Učinkovite tvari i pomoćne tvari otopimo u vodi pri 90°C, odnosno mikrokristaliničnu celulozu suspendiramo i disperziju uparimo u vakuumu. Suhu masu prosijemo na širinu petlja 1 mm. Granulatu učinkovite tvari primješamo za tabletu slijedeće sastojke: Dissolve the effective substances and auxiliary substances in water at 90°C, that is, suspend the microcrystalline cellulose and evaporate the dispersion in a vacuum. Sift the dry mass to a loop width of 1 mm. The following ingredients are mixed with the granule of the active substance for the tablet:
24,862 mg natrijeva karboksimetilškroba 24.862 mg sodium carboxymethyl starch
24,000 mg mikrokristalinične celuloze 24,000 mg of microcrystalline cellulose
0,500 mg magnezijeva stearata 0.500 mg magnesium stearate
50,000 mg 50,000 mg
Iz ove smjese sprešamo okrugle planparalelne tablete od 50 mg i promjera 5 mm. Round plan-parallel tablets of 50 mg and 5 mm in diameter are pressed from this mixture.
PRIMJER 14 EXAMPLE 14
Tablete s 0,5 mg AG-EE 623 ZW Tablets with 0.5 mg AG-EE 623 ZW
Jedna tableta sadrži: One tablet contains:
0,500 mg učinkovite tvari 0.500 mg of effective substance
0,250 mg N-metilglukamina 0.250 mg of N-methylglucamine
0,075 mg polivinilpirolidona 0.075 mg polyvinylpyrrolidone
0,150 mg polioksietilenpolioksipopilenskoga polimera 0.150 mg of polyoxyethylene polyoxypropylene polymer
0,300 mg mikrokristalinične celuloze 0.300 mg of microcrystalline cellulose
Priprava: Preparation:
Učinkovite tvari i pomoćne tvari otopimo u vodi pri 90°C, odnosno mikrokristaliničnu celulozu suspendiramo i disperziju uparimo u vakuumu. Suhu masu prosijemo na širinu petlja 1 mm. Dissolve the effective substances and auxiliary substances in water at 90°C, that is, suspend the microcrystalline cellulose and evaporate the dispersion in a vacuum. Sift the dry mass to a loop width of 1 mm.
Granulatu učinkovite tvari primješamo za tabletu slijedeće sastojke: The following ingredients are mixed with the granule of the active substance for the tablet:
24,225 mg natrijevakarboksimetil škroba 24.225 mg sodium carboxymethyl starch
24,000 mg mikrokristalinične celuloze 24,000 mg of microcrystalline cellulose
0,500 mg magnezijeva stearata 0.500 mg magnesium stearate
50,000 mg 50,000 mg
Iz ove smjese sprešamo okrugle planparalelne tablete od 50 mg i promjera 5 mm. Round plan-parallel tablets of 50 mg and 5 mm in diameter are pressed from this mixture.
PRIMJER 15 EXAMPLE 15
Tableta s 1,0 mg AG-EE 623 ZW Tablet with 1.0 mg AG-EE 623 ZW
Jedna tableta sadrži: One tablet contains:
1,00 mg učinkovite tvari 1.00 mg of active substance
0,05 mg N-metilglukamina 0.05 mg of N-methylglucamine
0,15 mg polivinilpirolidona 0.15 mg polyvinylpyrrolidone
0,03 mg polioksietilenpolioksipopilenskoga polimera 0.03 mg of polyoxyethylene polyoxypropylene polymer
0,60 mg mikrokristalinične celuloze 0.60 mg of microcrystalline cellulose
Priprava: Preparation:
Učinkovite tvari i pomoćne tvari otopimo u vodi pri 90°C, odnosno mikrokristaliničnu celulozu suspendiramo i disperziju uparimo u vakuumu. Suhu masu posijemo na širinu petlja 1 mm. Dissolve the effective substances and auxiliary substances in water at 90°C, that is, suspend the microcrystalline cellulose and evaporate the dispersion in a vacuum. Sow the dry mass to a loop width of 1 mm.
Granulatu učinkovite tvari primješamo za tabletu slijedeće sastojke: The following ingredients are mixed with the granule of the active substance for the tablet:
23,22 mg natrijevakarboksimetilškroba 23.22 mg sodium carboxymethyl starch
24,00 mg mikrokristalinične celuloze 24.00 mg microcrystalline cellulose
0,50 mg magnezijeva stearata 0.50 mg magnesium stearate
50,000 mg 50,000 mg
Iz ove smjese sprešamo okrugle planparalelne tablete od 50 mg promjera 5 mm. Round plan-parallel tablets of 50 mg with a diameter of 5 mm are formed from this mixture.
PRIMJER 16 EXAMPLE 16
Tableta s 1,5 mg AG-EE 623 ZW Tablet with 1.5 mg AG-EE 623 ZW
Jedna tableta sadrži: One tablet contains:
1,500 mg učinkovite tvari 1,500 mg of effective substance
0,750 mg N-metilglukamina 0.750 mg of N-methylglucamine
0,225 mg polivinilpirolidona 0.225 mg polyvinylpyrrolidone
0,045 mg polioksietilenpolioksipopilenskoga polimera 0.045 mg of polyoxyethylene polyoxypropylene polymer
0,900 mg mikrokristalinične celuloze 0.900 mg of microcrystalline cellulose
Priprava: Preparation:
Učinkovite tvari i pomoćne tvari otopimo u vodi pri 90°C, odnosno mikrokristaliničnu celulozu suspendiramo i disperziju uparimo u vakuumu. Suhu masu posijemo na širinu petlja 1 mm. Dissolve the effective substances and auxiliary substances in water at 90°C, that is, suspend the microcrystalline cellulose and evaporate the dispersion in a vacuum. Sow the dry mass to a loop width of 1 mm.
Granulatu učinkovite tvari primješamo za tabletu slijedeće sastojke: The following ingredients are mixed with the granule of the active substance for the tablet:
23,080 mg natrijeva karboksimetilškroba 23,080 mg sodium carboxymethyl starch
23,000 mg mikrokristalinične celuloze 23,000 mg of microcrystalline cellulose
0,500 mg magnezijeva stearata 0.500 mg magnesium stearate
50,000 mg 50,000 mg
Iz ove smjese sprešamo okrugle planparalelne tablete od 50 mg promjera 5 mm. Round plan-parallel tablets of 50 mg with a diameter of 5 mm are formed from this mixture.
PRIMJER 17 EXAMPLE 17
Tableta s 2,0 mg AG-EE 623 ZW Tablet with 2.0 mg AG-EE 623 ZW
Jedna tableta sadrži: One tablet contains:
2,00 mg učinkovite tvari 2.00 mg of active substance
1,00 mg L-lizina 1.00 mg of L-Lysine
1,00 mg polivinilpirolidona 1.00 mg polyvinylpyrrolidone
1,00 mg polioksietilenpolioksipopilenskoga polimera 1.00 mg of polyoxyethylene polyoxypropylene polymer
4,00 mg mikrokristalinične celuloze 4.00 mg of microcrystalline cellulose
Priprava: Preparation:
Učinkovite tvari i pomoćne tvari otopimo u vodi pri 90°C, odnosno mikrokristaliničnu celulozu suspendiramo i disperziju preradimo u difuznom sušioniku. Potom za tabletu dodajemo slijedeće sastojke: Effective substances and auxiliary substances are dissolved in water at 90°C, that is, microcrystalline cellulose is suspended and the dispersion is processed in a diffusion dryer. Then we add the following ingredients for the tablet:
20,35 mg mikrokristalinične celuloze 20.35 mg of microcrystalline cellulose
20,00 mg natrijeva karboksimetilškroba 20.00 mg sodium carboxymethyl starch
0,65 mg magnezijeva stearata 0.65 mg magnesium stearate
50,000 mg 50,000 mg
Iz ove smjese sprešamo okrugle bikonveksne tablete od 50 mg i promjera 5 mm, te ih preslojimo s hidroksipropilin etilcelulozom da se prekrije okus. From this mixture, round biconvex tablets of 50 mg and 5 mm in diameter are formed and layered with hydroxypropyl ethyl cellulose to cover the taste.
PRIMJER 18 EXAMPLE 18
Tableta s 2,5 mg AG-EE 623 ZW Tablet with 2.5 mg AG-EE 623 ZW
Jedna tableta sadrži: One tablet contains:
2,50 mg učinkovite tvari 2.50 mg of active substance
1,25 mg L-lizina 1.25 mg of L-lysine
1,25 mg polivinilpirolidona 1.25 mg of polyvinylpyrrolidone
1,25 mg polioksietilenpolioksipopilenskoga polimera 1.25 mg of polyoxyethylene polyoxypropylene polymer
4,10 mg mikrokristalinične celuloze 4.10 mg of microcrystalline cellulose
Priprava: Preparation:
Učinkovite tvari i pomoćne tvari otopimo u vodi pri 90°C, odnosno mikrokristaliničnu celulozu suspendiramo i disperziju preradimo u difuznom sušioniku. Za tabletu potom dodajemo slijedeće sastojke: Effective substances and auxiliary substances are dissolved in water at 90°C, that is, microcrystalline cellulose is suspended and the dispersion is processed in a diffusion dryer. For the tablet, we then add the following ingredients:
19,50 mg mikrokristalinične celuloze 19.50 mg of microcrystalline cellulose
19,50 mg natrijeva karboksimetilškroba 19.50 mg sodium carboxymethyl starch
0,65 mg magnezijeva stearata 0.65 mg magnesium stearate
50,000 mg 50,000 mg
Iz ove smjese sprešamo okrugle bikonveksne tablete od 50 mg i promjera 5 mm, te ih zbog prekrivanja okusa presvučemo hidroksipropilmetilcelulozom. Round biconvex tablets of 50 mg and 5 mm in diameter are formed from this mixture and coated with hydroxypropylmethylcellulose to mask the taste.
PRIMJER 19 EXAMPLE 19
Tableta s 3,0 mg AG-EE 623 ZW Tablet with 3.0 mg AG-EE 623 ZW
Jedna tableta sadrži: One tablet contains:
3,0 mg učinkovite tvari 3.0 mg of active substance
1,5 mg L-lizina 1.5 mg of L-lysine
1,5 mg polivinilpirolidona 1.5 mg polyvinylpyrrolidone
1,5 mg polioksietilenpolioksipopilenskoga polimera 1.5 mg of polyoxyethylene polyoxypropylene polymer
Priprava: Preparation:
Sastojke otopimo u vodi pri 90°C i otopinu preradimo u difuznom sušioniku. Za tabletu potom dodajemo slijedeće sastojke: Dissolve the ingredients in water at 90°C and process the solution in a diffusion dryer. For the tablet, we then add the following ingredients:
21,5 mg mikrokristalinične celuloze 21.5 mg of microcrystalline cellulose
21,0 mg natrijeva karboksimetilškroba 21.0 mg sodium carboxymethyl starch
50,00 mg 50.00 mg
Iz ove smjese sprešamo okrugle bikonveksne tablete od 50 mg i promjera 5 mm, te ih preslojimo s hidroksipropil-metilcelulozom da se prekrije okus. From this mixture, round biconvex tablets of 50 mg and 5 mm in diameter are formed, and we layer them with hydroxypropyl-methylcellulose to cover the taste.
PRIMJER 20 EXAMPLE 20
Tableta s 5 mg AG-EE 623 ZW Tablet with 5 mg AG-EE 623 ZW
Jedna tableta sadrži: One tablet contains:
5,0 mg učinkovite tvari 5.0 mg of active substance
2,5 mg L-lizina 2.5 mg of L-lysine
2,5 mg polivinilpirolidona 2.5 mg polyvinylpyrrolidone
2,5 mg polioksietilenpolioksipopilenskoga polimera 2.5 mg of polyoxyethylene polyoxypropylene polymer
Priprava: Preparation:
Sastojke otopimo u vodi pri 90°C, i otopinu preradimo u difuznom sušioniku. Za tabletu potom dodajemo slijedeće sastojke: Dissolve the ingredients in water at 90°C, and process the solution in a diffusion dryer. For the tablet, we then add the following ingredients:
19,0 mg mikrokristalinične celuloze 19.0 mg of microcrystalline cellulose
18,5 mg natrijeva karboksimetilškroba 18.5 mg sodium carboxymethyl starch
50,0 mg 50.0 mg
Iz ove smjese sprešamo okrugle bikonveksne tablete od 50 mg i promjera 5 mm, te ih preslojimo s hidroksipropil-metilcelulozom za prekrivanje okusa. From this mixture, round biconvex tablets of 50 mg and 5 mm in diameter are formed, and we layer them with hydroxypropyl-methylcellulose to cover the taste.
Claims (11)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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HR940769A HRP940769B1 (en) | 1991-06-28 | 1994-10-25 | (s)(+)-2-ethoxy-4-(n-(1-(2-piperidinophenyl)-3-methyl-1-butyl)-aminocarbonylmethyl)benzoic acid, medicines containing them, that compound and processes for the preparation thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
YU113691A YU48052B (en) | 1991-06-28 | 1991-06-28 | (S) - (+) - 2-ETHOXY-4- / N- (1- (2-PIPERIDINO-PHENYL) -3-METHYL-1-BUTYL-AMINOCARBONYL-METHYL-benzoic acid and procedures for its preparation |
HR940769A HRP940769B1 (en) | 1991-06-28 | 1994-10-25 | (s)(+)-2-ethoxy-4-(n-(1-(2-piperidinophenyl)-3-methyl-1-butyl)-aminocarbonylmethyl)benzoic acid, medicines containing them, that compound and processes for the preparation thereof |
Publications (2)
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HRP940769A2 true HRP940769A2 (en) | 1997-08-31 |
HRP940769B1 HRP940769B1 (en) | 2001-04-30 |
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HR940769A HRP940769B1 (en) | 1991-06-28 | 1994-10-25 | (s)(+)-2-ethoxy-4-(n-(1-(2-piperidinophenyl)-3-methyl-1-butyl)-aminocarbonylmethyl)benzoic acid, medicines containing them, that compound and processes for the preparation thereof |
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HR (1) | HRP940769B1 (en) |
Cited By (1)
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CN109970681A (en) * | 2019-04-19 | 2019-07-05 | 安徽海康药业有限责任公司 | A kind of synthetic method of Repaglinide |
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1994
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN109970681A (en) * | 2019-04-19 | 2019-07-05 | 安徽海康药业有限责任公司 | A kind of synthetic method of Repaglinide |
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